WO2006082404A1 - Compounds having tie2 (tek) inhibitory activity - Google Patents

Compounds having tie2 (tek) inhibitory activity Download PDF

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Publication number
WO2006082404A1
WO2006082404A1 PCT/GB2006/000352 GB2006000352W WO2006082404A1 WO 2006082404 A1 WO2006082404 A1 WO 2006082404A1 GB 2006000352 W GB2006000352 W GB 2006000352W WO 2006082404 A1 WO2006082404 A1 WO 2006082404A1
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alkyl
formula
group
alkoxy
compound
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PCT/GB2006/000352
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French (fr)
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Clifford David Jones
Richard William Arthur Luke
William Mccoull
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to EP06709603A priority Critical patent/EP1848715A1/en
Priority to JP2007553692A priority patent/JP2008535780A/en
Priority to US11/815,523 priority patent/US20080153838A1/en
Publication of WO2006082404A1 publication Critical patent/WO2006082404A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to compounds, or pharmaceutically acceptable salts thereof, which possess anti-angiogenic activity and are accordingly useful in methods of treatment of disease states associated with angiogenesis in the animal or human body.
  • the invention also concerns processes for the preparation of the compounds, pharmaceutical compositions containing the compounds as active ingredient, and methods for the use of the compounds in the manufacture of medicaments for use in the production of anti- angiogenic effects in warm-blooded animals such as humans.
  • the Tie2 receptor tyrosine kinase also known as TEK
  • TEK Tie2 receptor tyrosine kinase
  • Angiogenesis is a fundamental process defined as the generation of new blood vessels from existing vasculature. It is a vital yet complex biological process required for the formation and physiological functions of virtually all the organs. Normally it is transient in nature and is controlled by the local balance of angiogenic and angiostatic factors in a multi-step process involving vessel sprouting, branching and tubule formation by endothelial cells (involving processes such as activation of endothelial cells (ECs), vessel destabilisation, synthesis and release of degradative enzymes, EC migration, EC proliferation, EC organisation and differentiation and vessel maturation).
  • endothelial cells involving processes such as activation of endothelial cells (ECs), vessel destabilisation, synthesis and release of degradative enzymes, EC migration, EC proliferation, EC organisation and differentiation and vessel maturation).
  • angiogenesis plays an important role in a variety of processes and is under stringent control. In the adult, physiological angiogenesis is largely confined to wound healing and several components of female reproductive function and embryonic development. In undesirable or pathological angiogenesis, the local balance between angiogenic and angiostatic factors is dysregulated leading to inappropriate and/or structurally abnormal blood vessel formation. Pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacology. Science. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31).
  • VEGF vascular endothelial growth factor
  • polypeptide moieties interact with their respective receptors (transmembrane tyrosine kinases which are predominantly endothelial cell specific) and induce cellular responses via ligand mediated signal transduction. It has been speculated that VEGF and the angiopoietins co-operate to regulate various aspects of the angiogenic process during both normal and pathological angiogenesis via signalling through their respective receptors.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.
  • fms-like tyrosine kinase receptor Fit or Fltl
  • KDR kinase insert domain-containing receptor
  • Flt4 Flt4
  • Two of these related RTKs, Fit and KDR have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
  • Tie receptors and their ligands co-operate closely with VEGF during both normal and pathological angiogenesis.
  • the transmembrane receptors Tiel and Tie2 constitute a family of endothelial cell specific tyrosine kinase receptors involved in maintenance of blood vessel integrity and which are involved in angiogenic outgrowth and vessel remodelling. Structurally Tiel and Tie2 share a number of features (e.g.
  • the intracellular domains of both these receptors each contain a tyrosine kinase domain interrupted by a kinase insert region) and thus constitute a distinct RTK subfamily.
  • Overall sequence identity between Tiel and Tie2 receptors at the amino acid level is 44% while their intracellular domains exhibit 76% homology.
  • Targeted disruption of the Tiel gene results in a lethal phenotype characterised by extensive haemorrhage and poor microvessel integrity (Puri, M. et al. 1995 EMBO Journal: 14:5884-5891).
  • Transgenic mice deficient in Tie2 display defects in vessel sprouting and remodelling and display a lethal phenotype in mid gestation (E9.5- 10.5) caused by severe defects in embryonic vasculature (Sato, T. et al. 1995 Nature 370: 70-74).
  • Tiel is believed to influence Tie2 signalling via heterodimerisation with the Tie2 receptor hence potentially modulating the ability of Tie2 to autophosphorylate (Marron, M. et al. 2000 Journal of Biological Chemistry: 275, 39741- 39746) and recent chimaeric Tiel receptor studies have indicated that Tie-1 may inhibit apoptosis via the PI 3 kinase/Akt signal transduction pathway (Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713).
  • angiopoietins a number of ligands, designated the angiopoietins have been identified for Tie2 of which Angiopoietin 1 (Angl) is the best characterised. Binding of Angl induces tyrosine phosphorylation of the Tie2 receptor via autophosphorylation and subsequently activation of its signalling pathways via signal transduction. Ang2 has been reported to antagonise these effects in endothelial cells (Maisonpierre, P. et al. 1997 Science: 277, 55-60). The knock-out and transgenic manipulation of Tie2 and its ligands suggest that stringent spatial and temporal control of Tie2 signalling is imperative for the correct development of new vasculature.
  • Activation of the Tie2 receptor by Angl inhibits apoptosis (Papapetropoulos, A., et al., 2000 Journal of Biological Chemistry : 275 9102-9105), promotes sprouting in vascular endothelial cells (Witzenbicher, B., et al., 1998 Journal of Biological Chemistry: 273, 18514-18521) and in vivo promotes blood vessel maturation during angiogenesis and reduces the permeability and consequent leakage from adult microvessels (Thurston, G. et al., 2000 Nature Medicine: 6, 460-463).
  • Tie2 receptor is reported to be involved in the branching, sprouting and outgrowth of new vessels and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and overall appears to be consistent with promoting microvessel stability. Absence of Tie2 activation or inhibition of Tie2 auto phosphorylation may lead to a loss of vascular structure and matrix/cell contacts (Thurston, G., Cell Tissue Res (2003), 314: 61-69) and in turn may trigger endothelial cell death, especially in the absence of survival or growth stimuli.
  • Tie2 kinase activity may provide an anti-angiogenic effect and thus have application in the therapy of disease states associated with pathological angiogenesis.
  • Tie2 expression has been shown to be up- regulated in the neovasculature of a variety of tumours (e.g. Peters, K.G. et al, British Journal of Cancer 1998; 77,51-56) suggesting that inhibiting Tie2 kinase activity will result in anti-angiogenic activity.
  • studies with soluble Tie2 receptor extracellular domain
  • VM venous malformation
  • VM's are commonly found in the skin or mucosal membranes but can affect any organ.
  • lesions appear as spongy, blue to purple vascular masses composed of numerous dilated vascular channels lined by endothelial cells.
  • Tie2 kinase mutation C2545T in the Tie2 coding sequence (Calvert, J.T., et al., 1999 Human Molecular genetics: 8, 1279-1289), which produces a R849W amino acid substitution in the kinase domain.
  • Analysis of this Tie2 mutant indicates that it is constitutively activated even in the absence of ligand (Vikkula, M., et al, 1996 Cell: 87, 1181-1190).
  • Upregulation of Tie2 expression has also been found within the vascular synovial pannus of arthritic joints in humans, which is consistent with the role of inappropriate neovascularisation.
  • A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
  • B represents a (3-7C)cycloallcyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur and which is saturated, partially saturated or aromatic;
  • D represents 5 or 6 membered nitrogen-containing heteroaryl ring which optionally comprises 1 or 2 or 3 further heteroatoms independently selected from oxygen, nitrogen or sulphur;
  • L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R 8 )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, -C(R a R b )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, -C(R a R b )N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) r , -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y -, -C(O)N(R 9 )-(CR a R b ) x -Z-(CR a
  • R 1 is selected from hydrogen, hydroxy, (l-6C)alkyl, (l-6C)alkoxy or (3-7C)cycloalkyl wherein the (l ⁇ 6C)alkyl, (l-6C)alkoxy and the (3-7C)cycloalkyl groups are optionally substituted by one or more groups independently selected from halo, hydroxy, (l-6C)alkyl, (l- ⁇ C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy
  • p 0, 1, 2 or 3;
  • R 2 and R 3 are independently selected from hydrogen, (l- ⁇ C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2) v - in which v is 0, 1, 2, 3, 4, 5 or 6 , or a 5 or 6 membered heteroaryl ring, or R 2 and R 3 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein a (l-6C)alkyl, the (l-6C)alkoxy, the (l-6C)alkanoyl and the (3- 6C)cycloalkyl groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl
  • R 5 is selected from cyclopropyl, cyano, halo, (l-6C)alkoxy or (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or by one or more fluoro;
  • n 0, 1, 2 or 3;
  • R 6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, -S(O) q -(l-6C)alkyl wherein q is 0, 1 or 2, -N(R c )C(O)(l-6C)alkyl in which R c is hydrogen or (l-6C)alkyl; or R 6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl,
  • -S(O) q -(l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl]amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl or hydroxy(l-6C)alkyl; and m is 0, 1, 2 or 3;
  • B is a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10 membered bicyclic group
  • the rings and bicyclic group optionally bear 1 or 2 oxo or thioxo substituents; and salts or solvates thereof.
  • L represents -C(R a R b )C(O)N(R 9 )-, -N(R 8 )C(O)C(R a R b )-, -N(R 8 )C(O)N(R 9 )-,
  • D is pyrimidin-5-yl
  • the 2-position of the pyrimidinyl-5-yl is substituted by -NR 2 R 3
  • both the 4-position and 6-position of the pyrimidin-5-yl must be substituted by -NR 2 R 3 , in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
  • the invention provides the use of a compound of formula (I) as defined above, but subject to the following alternative provisos: that: (i') when D is pyrimidin-5-yl, the 4-position of the pyrimidin-5-yl is substituted by R 1 , the 6-position of the pyrimidin-5-yl is substituted by -NR 2 R 3 , and L is
  • the invention provides the use of a compound of formula (I) as defined above, but with the proviso that when L is a group -C(O)N(R 9 )- (CR a R b ) x -Z-(CR a R b ) y -, then at least one of x or y is other than 0, or Z is other than a direct bond, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
  • the invention provides the use of a compound of formula (I) as defined above, but with the proviso that when L is a group
  • p is at least 1 and at least one R 1 group is other than unsubstituted (l-6C)alkyl, unsubstituted (l-6C)alkoxy or hydroxy, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
  • the invention provides the use of a compound of formula (I) as defined above, where L is a group -N(R 8 )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) r , in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man
  • L is shown, the left hand side of the formula represented is attached to the ring A and the ring hand side is attached to ring B.
  • L is a group -N(R 8 )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, the moiety
  • D is other than an NR 2 R 3 substituted fully unsaturated pyrimidin-5-yl although it may be a hydrogenated form of pyrimidin-5-yl such as dihydro- pyrimidin-5-yl, and it may carry other R 1 substituent groups.
  • D is unsubstituted pyrimidin-5-yl.
  • alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as "isopropyl” are specific for the branched-chain version only.
  • (l- ⁇ C)alkoxy includes methoxy, ethoxy and isopropoxy
  • (l-6C)alkylamino includes methylamino
  • di-[(l-6Calkyl]amino includes dimethylamino, diethylamino andN-methyl-N-isoproylamino
  • aryl refers to phenyl or naphthyl, particularly phenyl.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • Suitable values for the generic radicals referred to above include those set out below.
  • Suitable 5 or 6 membered heteroaryl rings include, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl or pyrazinyl.
  • Particular 5 or 6 membered heteroaryl rings include imidazolyl, pyridyl, thiazolyl, thiadiazolyl, pyrimidinyl, isoxazolyl, pyrazolyl and isothiazolyl.
  • Suitable saturated or partially saturated 3 to 7 membered heterocyclic rings include, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3- thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3-azabicyclo[3.1.1]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro-1,4- thiazinyl, 1-oxotetrahydrothienyl, l,l-dioxotetrahydro-l,
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2- oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5- dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • the saturated or partially saturated 3 to 7 membered heterocyclic rings are optionally substituted by one or more (l-6C)alkyl groups and/or by one or more hydroxy.
  • this definition includes tautomers of hydroxy substituted ring systems where the hydroxy tautomerizes to an oxo group.
  • Suitable 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, imidazolo[2, 1 -b]thiazolyl, dihydrocyclopentathiazolyl, tetrahydrocyclopenta[c]pyrazolyl, furo[3,2-b]furanyl, pyrrolopyrrole, thienopyrazolyl, thieno[2,3-b]thiophenyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[b]furanyl, benzo[b]thiophenyl, IH- indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxal
  • Particular 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[b]furanyl, benzo[b]thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indenyl, naphthalenyl, 2,3-dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-yl.
  • the bicyclic group is optionally substituted by one or more groups R 6 as hereinbefore defined.
  • Suitable 5 or 6 membered nitrogen-containing heteroaryl ring which optionally further comprises 1 or 2 further heteroatoms independently selected from oxygen, nitrogen or sulphur include: pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl
  • the group A may particularly be attached to the ethynyl group via a carbon atom in the aryl group or in the 5 or 6 membered heteroaryl ring.
  • the group B may particularly be attached to the group L via a carbon atom.
  • Suitable values for any of the substituents herein, for example the 'R' groups (R 1 to R 11 ) or for various groups within a A, B or L group include: for halo fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l-6C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-
  • the invention relates to all tautomeric forms of the compounds of the formula I forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
  • a suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid-addition salt of a compound of the formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a compound of the formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid
  • a salt of a compound of the formula I which is sufficiently acidic
  • pro-drugs of compounds of the invention as herein before or herein after defined.
  • Compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I).
  • pro-drugs include in-vivo hydroly sable esters of a compound of the Formula (I).
  • pro-drugs are known in the art.
  • An in- vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pha ⁇ naceutically-acceptable esters for carboxy include Ci. 6 alkoxymeth.yl esters for example methoxymethyl, Ci- 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters,
  • C 3-8 cycloalkoxycarbonyloxyCi. 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci -6 alkoxycarbonyloxyethyl esters.
  • An in- vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in- vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • Particular compounds of formula (I) include, for example, compounds of the formula I, or salts, particularly pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, L, m and n has any of the meanings defined hereinbefore or in paragraphs (a) to (11111) hereinafter: - (a) L is attached meta on ring A with respect to the point of attachment of the ethynyl group;
  • L is attached para on ring A with respect to the point of attachment of the ethynyl group;
  • L is -N(R 8 )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b )y wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b , R 8 and R 9 are independently selected from hydrogen and (l- ⁇ C)alkyl (particularly R a , R b , R 8 and R 9 are all hydrogen );
  • (b') L is -N(R 8 )C(O)N(R 9 )-(CR a R b ) x - wherein x is as defined above, (particularly x is 1 or 2) and R a , R b , R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl
  • (b") L is -N(R 8 )C(O)N(R 9 )-CR a R b - wherein R a , R b , R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b , R 8 and R 9 are all hydrogen );
  • (b" ') L is -N(R 8 )C(O)N(R 9 )-CH 2 - wherein R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R 8 and R 9 are both hydrogen );
  • (b" ") L is -N(R 8 )C(O)N(R 9 )-(CR a R b ) ⁇ -O-(CR a R b ) y - wherein x and y are as defined above, and R a , R b , R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl
  • (b'"") L is -N(R 8 )C(O)N(R 9 HCR a R b ) ⁇ -N(R 8 )-(CR a R b ) y - wherein R ⁇ R b , R 8 and R 9 are independently selected from hydrogen and (l- ⁇ C)alkyl (particularly R a , R b , R 8 and R 9 are all hydrogen );
  • R b , R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a ,
  • R b , R 8 and R 9 are all hydrogen );
  • L is -N(R 8 )C(O)-(CR a R b ) ⁇ -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b R 8 and R 9 are all hydrogen );
  • (c') L is -N(R 8 )C(O)-(CR a R b ) x - wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen);
  • L is -N(R 8 )C(O)-CR a R b - wherein R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (c" ') L is -N(R 8 )C(O)-CH 2 - wherein R 8 is selected from hydrogen and (l-6C)alkyl
  • L is ⁇ C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (d') L is -C(O)N(R 9 )-(CR a R b ) x - wherein x is as defined above, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen);
  • L is -C(O)N(R 9 )-CR a R b - wherein R a , R b and R 9 are independently selected from hydrogen and (l- ⁇ C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • L is -C(O)N(R 9 )-CH 2 - wherein R 9 is selected from hydrogen and (1 -6C)alkyl (particularly R 9 is hydrogen );
  • L is ⁇ N(R 8 )C(O)-O-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R s are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • L is -N(R 8 )C(O)-O-(CR a R b ) x - wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen);
  • L is -N(R 8 )C(O)-O-CR a R b - wherein R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (e' ") L is -N(R 8 )C(O)-O-CH 2 - wherein R 8 is selected from hydrogen and (1 -6C)alkyl (particularly R 8 is hydrogen );
  • L is -O-C(O)-N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (f ) L is -O-C(O)N(R 9 )-(CR a R b ) x - wherein x is as defined above, and R a , R b and R 9 are independently selected from hydrogen and (1 -6C)alkyl (particularly R a , R b and R 9 are all hydrogen);
  • (f ') L is -O-C(O)N(R 9 )-CR a R b - wherein R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • L is -O-C(O)N(R 9 )-CH 2 - wherein R 9 is selected from hydrogen and (l-6C)alkyl (particularly R 9 is hydrogen );
  • L is -N(R 8 )S(O) 2 -(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and
  • Z is -O- or -N(H)-, and R a , R b and R 8 are independently selected from hydrogen and
  • (g') L is -N(R 8 )S(O) 2 -(CR a R b ) ⁇ - wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen);
  • (g' ') L is -N(R 8 )S(O) 2 -CR a R b - wherein R a , R b and R 8 are independently selected from hydrogen and (l- ⁇ C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (g" ') L is -N(R 8 )S(O) 2 -CH 2 - wherein R 8 is selected from hydrogen and (l-6C)alkyl (particularly R 8 is hydrogen );
  • (h) L is -S(O) 2 N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and
  • Z is -O- or -N(H)-, and R a , R b and R 9 are independently selected from hydrogen and
  • (h') L is -S(O) 2 N(R 9 )-(CR a R b ) x - wherein x is as defined above, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen);
  • (h) L is -S(O) 2 N(R 9 )-CR a R b - wherein R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (h' ') L is -S(O) 2 N(R 9 )-CH 2 - wherein R 9 is selected from hydrogen and (l-6C)alkyl (particularly R 9 is hydrogen );
  • L is -N(R 8 )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, wherein x is as defined above, and
  • R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a ,
  • R b and R 8 are all hydrogen); Particularly L is -N(H)C(O)N(H)-;
  • R a and R b represent hydrogen;
  • R a and R b independently represent hydrogen or (l-6C)alkyl, wherein a (l-6C)alkyl group in R a and R b is optionally substituted by hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring;
  • R a and R b independently represent hydrogen or (1 -6C)alkyl, wherein a (l-6C)alkyl group in R a and R b is optionally substituted by hydroxy or a saturated or partially saturated 5 to 6 membererd heterocyclic ring;
  • R a and R b independently represent hydrogen, methyl or ethyl, wherein a (l-6C)alkyl group in R a and R b is optionally substituted by hydroxy or pyrrolin-1-yl;
  • (k) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl;
  • (k') A is selected from phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl;
  • (k) A is phenyl or pyridyl
  • (k' ") A is phenyl or pyridyl, wherein the nitrogen in the pyridyl ring is in the 3-position relateive to the alkyne bond;. (k “ " ) A is phenyl or thizolyl ;
  • (k'") A is phenyl, pyridyl, thiazolyl, or thiadiazolyl
  • A is phenyl
  • (n) A is phenyl or pyridyl and n is 0;
  • (n 1 ) A is phenyl or thizolyl and n is 0;
  • A is thiazolyl and n is 0 or n is 1 and R 5 is (1 -4C)alkyl;
  • A is phenyl and n is 0 or n is 1 and R 5 is (l-4C)alkyl;
  • p A is pyridyl and n is 0 or n is 1 and R 5 is (l-4C)alkyl;
  • (q) A is selected from phenyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl and pyrimidyl.
  • B When B is a (3-7C)cycloalkyl ring then B is selected grom cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (s) When B is a saturated or partially saturated 3 to 7 membered heterocyclic ring then B is selected from oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, , morpholinyl, 1,3- dioxolanyl, tetrahydrofuranyl, piperidyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, homopiperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, tetrahydropyridinyl, 1,2,4-oxadiazolyl and dihydrothiopyranyl; (t) When B is a 5 or 6 membered hetero
  • B is an 8, 9 or 10 membered bicyclic group which optionally contains 1,2,3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic then B is selected from 2,3-dihydro-lH-indenyl, benzodioxinyl, 1 ,2,3 ,4-tetrahydrona ⁇ hthalenyl, 1 ,2,3 ,4-tetrahydropentalene, benzofuranyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzthienyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, indolyl, and naphth
  • W is a 5-7 membered ring (including the bridging atoms), said W ring comprising carbon atoms or optionally further heteroatoms independently selected from oxygen, nitrogen and sulphur, wherein said bicyclic ring contains no more that 4 heteroatoms in total.
  • Such rings include: pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5- c]pyrimidinyl, pyrazolo[l,5-a][l,3,5]triazinyl, 4,5-dihydropyrazolo[l,5-a]pyridmyl, 4H-pyrazolo[5, 1 -c] [1 ,4]thiazinyl, 4H-pyrazolo[5, 1 -c] [1 ,4]oxazinyl, 1 ,2-benzisoxazolyl, isoxazolo [5 ,4-b]pyridinyl, isoxazolo [5 ,4-d]pyrimidinyl, 4H-thiopyrano [3 ,4-d] isoxazolyl, 4H-pyrano[3,4-d]isoxazolyl, 7aH-indolyl, 7aH-pyrrolo
  • (v) B is aryl, particularly phenyl;
  • (w) B is a saturated or partially saturated 3 to 7 (particularly 4 to 6) membered heterocyclic ring that contains one or two heteroatoms (particularly one heteroatom) selected from oxygen and nitrogen;
  • (x) B is a a 5 or 6 membered heteroaryl ring;
  • (y) B is a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2 or 3 (particularly 1 or 2) heteroatoms independently selected from N and O and which is saturated, partially saturated or aromatic;
  • (z) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S
  • (aa) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl;
  • (bb) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
  • (cc) B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, pyrrolidinyl, piperidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3 ⁇ dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-
  • B is isoxazolyl; (ee) B is selected from phenyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl.
  • (ee') B is selected from phenyl, cyclohexyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl.
  • (ff) B is selected from piperidinyl, phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl;
  • (gg) B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • Gj) B is phenyl
  • (H') D is selected from pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl.
  • (H) D is selected from oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.
  • (U') D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
  • (H") D is selected from thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.
  • the ring D has a nitrogen atom at the meta position with respect to the alkynyl group in Formula I.
  • R and R are independently selected from hydrogen, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l- ⁇ C)alkyl, (l-6C)alkoxycarbonyl, (3- 6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy,
  • R 2 is hydrogen and R 3 is selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1- 6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (l-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroary
  • (ss) R 2 and R 3 are independently selected from hydrogen, (l- ⁇ C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or
  • R 2 and R 3 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 2 and/or R 3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R and R are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, or a 5 or 6 membered heteroaryl ring; wherein the (l- ⁇ C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 2 and/or R 3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R 2 is hydrogen and R 3 is selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1- 6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and
  • R 2 is hydrogen and R 3 is selected from hydrogen, (1 -6C)alkanoyl, (1 -6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R 2 is hydrogen and R 3 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R 2 is hydrogen and R 3 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R 2 is hydrogen and R 3 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkoxy, amino, mono(l-3C)alkylamino, di(l-3C)alkylamino, carbamoyl or-N(R d )C(O)(l-3C)alkyl in which R d is hydrogen or (l-3C)alkyl, or a saturated 5 or 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-4C)alkoxy and (l-4C)alkoxy(l-4C)alkoxy and the (1- 3C)alkyl groups of
  • R 2 is hydrogen and R 3 is selected from hydrogen and (l- ⁇ C)alkyl (particularly (l-3C)alkyl); wherein the (l- ⁇ C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R 3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); (ccc) R 2 is hydrogen and R 3 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R 3 are optionally independently substituted
  • R 2 is hydrogen and R 3 is selected from hydrogen, acetyl or methoxyethyoxymethyl;
  • R 2 and R 3 are both hydrogen or R 1 is hydrogen or (l-6C)alkyl and R 2 is (l-6C)alkyl or (l-6C)alkanoyl; wherein (l-6Calkyl) or (l-6C)alkanoyl is optionally substituted by hydroxy, amino, mono(l-6C)alkylamino or di(l-6C)alkylamino, carbamoyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, -N(R d )C(O)(l-6C)alkyl in which R d is hydrogen or
  • R 2 and R 3 are independently selected from hydrogen, methyl, ethyl, propyl, acetyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino) ethyl, 3-(isopropylamino)propyl, 2-
  • R 2 is hydrogen and R 3 is selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3- carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholin-4-ylethyl, 3-morpholin-4- ylpropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-yl ⁇ ropyl, 3-(4-methylpiperazin-l- yl)propyl, 3-piperidin-l-yl-yl
  • R 1 is hydrogen and R 2 is selected from R 2 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is substituted by a saturated 5 or 6 membered heterocyclic ring;
  • R 1 is hydrogen and R 2 is selected from 2-morpholino-4-yl-ethyl or 3-morpholinyl- 4-ylpropyl;
  • R 2 is hydrogen or methyl and R 3 is selected from hydrogen, methyl, 2- hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-(2-hydroxyethoxy)ethyl, 2- methoxyethoxymethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-
  • R 2 is hydrogen and R 3 is selected from 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyL 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-pyrrolidin-l- ylethyl, 4-methyl-piperazin-l -ylpropyl and 3 -pyrrolidin-1 -ylpropyl;
  • R 2 is hydrogen and R 3 is selected from 2-morpholin-4-ylethyl, 3-mor ⁇ holin-4-ylpropyl, 3-piperidin-l-ylpropyl, 2- ⁇ iperidin-l-ylethyl, 2-pyrrolidin-l- ylethyl, 3-pyrrolidin-l-ylpropyl and 4-methyl-piperazin-l-yl;
  • R 2 and R 3 are both (l-6C)alkyl (particularly (l-3C)alkyl); (111) R 2 is hydrogen and R 3 is methyl;
  • R 1 is selected from hydrogen, (l-3C)alkyl or (l-3C)alkoxy, wherein the (l-3C)alkyl and the (l-3C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l- 6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl,
  • (qqq) p is 0 or p is 1, 2 or 3 and R 3 is independently selected from hydroxy and (l-6C)alkoxy or a group -NR 2 R 3 as defined above (particularly -NH 2 ); Or ⁇ l') p is 0 or p is 1 and R 3 is independently selected from hydroxy and (l-6C)alkoxy or a group -NR 2 R 3 as defined above (particularly -NH 2 );
  • R 1 is selected from hydrogen or a group -NR 2 R 3 as defined above (particularly -NH 2 );
  • R 1 is selected from hydrogen or -NH 2 .
  • R 1 is independently selected from (l-6C)alkyl (particularly (l-3C)alkyl);
  • (sss) R 5 is selected from (l-6C)alkyl and (l-6C)alkoxy;
  • (ttt) R 5 is selected from ( 1 -4C)alkyl and ( 1 -4C)alkoxy ;
  • R 5 is selected from methyl and methoxy
  • (vw) n is 0, 1 or 2 (particularly 0 or 1, more particularly 0); (www) n is 1 or 2 and R 5 is independently selected from halo, (l-6C)alkoxy and (1- 6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fiuoro;
  • R 5 is independently selected from cyano, halo, (l-6C)alkoxy and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fiuoro;
  • (yyy) n is 0 or I and when n is 1, R 5 is (l-4C)alkyl (particularly methyl);
  • (zzz) n is 1 or 2 and R 5 is independently selected from cyclopropyl and (l-6C)alkyl, wherein the (l-6C)alkyl groups are optionally substituted by cyano or one or more fiuoro;
  • (aaaa) n is 1 and R 5 is (l-6C)alkyl, particularly (l-3C)alkyl; (bbbb) n is 0
  • R 6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(R c )C(O)(l-6C)alkyl in which R° is hydrogen or (l-6C)alkyl; or R 6 is selected from (l- ⁇ C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l- 6C)alkyl]amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring;
  • R 6 is independently selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or an -N(R c )C(O)(l-6C)alkyl in which R° is hydrogen or (l-6C)alkyl; or R 6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1-or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro);
  • R 6 is independently selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(R c )C(O)(l-6C)alkyl in which R c is hydrogen or (l-3C)alkyl; or R 6 is selected from (l-4C)alkyl or (l-4C)alkoxy, wherein the (l-4C)alkyl and the (l-4C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro); (ggg) R 6 is selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy
  • R 6 is selected from fluoro, chloro, acetylamino, methyl, propyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy and morpholin-4-yl; [exemplification in this case] (iiii) R 6 is independently selected from (l-6C)alkyl, (l-6C)alkoxy or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl or piperidin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by hydroxy (l-2C)alkyl; (iiii') R 6 is independently selected from hydroxy, halo (particularly chloro or fluoro), (l-6C)alkyl, (l-6C)alkoxy
  • (liii' ') R 6 is independently selected from (l-6C)alkyl (optionally substituted 1 to 3 groups independently selected from halo, particularly fluoro), halo or (l-6C)alkoxy; (iiii'") R 6 is independently selected from (l-6C)alkyl;
  • R 6 is independently selected from methyl, trifluoromethyl, morpholin-4-yl or piperidin- 1 -yl, 4-hydroxymethylpiperidin- 1 -yl;
  • R 6 is independently selected from methyl, methoxy, di-methylamino, hydroxy, oxo, chloro, fluoro, trifluoromethyl, morpholin-4-yl or piperidin- 1-yl, 4-hydroxymethylpiperidin- 1-yl, 4-methylpiperzin-l-yl;
  • R 6 is independently selected from chloro, fluoro, trifluoromethyl, methyl or methoxy;
  • R 6 is independently selected from t-butyl
  • R 6 is independently selected from halo, trifluoromethyl, methyl, tert-butyl, methoxy, acetylamino or morpholino.
  • R 6 is independently selected from halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(R c )C(O)(l-6C)alkyl wherein R c is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or (1 -6C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro).
  • R 6 is independently selected from hydroxy, halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(R c )C(O)(l-6C)alkyl wherein R c is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by a saturated 3 to 7 membered heterocyclic ring or up to three groups independently selected from halo, particularly fluoro), (l-6C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or di-(l-6C)alkylamino;.
  • R 6 is independently selected from halo, trifluoromethyl, cyano, methyl, isopropyl, tert-butyl, methoxy, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1- yl, 4-(hydroxymethyl)piperidin- 1 -yl and 4-methyl-piperazin- 1 -yl.
  • R 6 is independently selected from hydroxy, halo, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, 1-cyanoethyl, methoxy, isopropoxy, di-methylamino, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1-yl, 4-(hydroxymethyl)piperidin-l-yl, 4-methyl-piperazin-l-yl and 4-methylpiperazin-l- ylmethyl
  • R 6 is independently selected from halo (such as chloro), trifluoromethyl, methoxy, dimethylamino, morpholin-4-yl or piperidin-1-yl;
  • At least one R 6 group is selected from amino, mono(Ci-6alkyl)amino, di-(Ci-6- alkyl)amino such as dimethylamino; (nnnn) m is 1 or 2; (oooo) m is 1;
  • (qqqq) Ring B-R 6 where m is 1 or 2, is selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin- 1 -yl, 2-morpholin-4-ylphenyl, 2-(piperidin-l-yl)phenyl, 2-[4-(hydroxymethyl)piperidin-l-yl)]phenyl, 5-methyl-furan-2-yl and 4-morpholin-4-ylpyrimidin-5 -yl;
  • Ring B-R 6 where m is 1 or 2, is selected from: 2-hydroxycyclohexyl, 2-methylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2- (dimethylamine)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin- 1-yl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, morpholin-4-yl-5- fluorophenyl, 2-(piperidin-l-yl)phenyl, 2-[4-(hydroxymethyl)piperidin-l-yl)]phenyl, 5-methyl-furan-2-yl, 2-(4-methylpiperzin-l-yl)phenyl and 4-morpholin-4-ylpyrimidin-5-yl; (qqqq'") Ring B-R 6 , where m is 1 or 2, is selected from: 2-hydroxycyclohexy
  • Ring B-R 6 where m is 1 or 2, is selected from
  • (ssss) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and Lis attached meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R 8 )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) r or -N(
  • Z is a direct bond, -O- or -N(R 8 )- x and y are independently 0, 1, 2 or 3, with the proviso that x+y ⁇ 4,
  • R 8 , R 9 , R a and R b represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in R a and R b is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
  • (tttt) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and
  • Z is a direct bond, -O- or -N(R 8 )- x and y are independently 0, 1, 2 or 3, with the proviso that x+y ⁇ 4,
  • R 8 , R 9 , R a and R b represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in R a and R b is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
  • D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
  • (uuuu) A is phenyl; n is 0; and B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or
  • B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • (wwww)A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
  • Z is a direct bond, -O- or -N(R 8 )- x and y are independently 0, 1, 2 or 3, with the proviso that x+y ⁇ 4,
  • R 8 , R 9 , R a and R b represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in R a and R b is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
  • B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
  • Z is a direct bond, -O- or -N(R 8 )- x and y are independently 0, 1, 2 or 3, with the proviso that x+y ⁇ 4,
  • R 8 , R 9 , R a and R b represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in R a and R b is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
  • B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • (yyyy) m is 0, I or 2 (particularly 1 or 2);
  • (zzzz) B is selected from cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • (aaaaa) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
  • R 6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(R c )C(O)(l-6C)alkyl in which R c is hydrogen or (l-6C)alkyl; or R 6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l- ⁇ C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro);
  • (bbbbb) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • (ccccc) B is phenyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • (ddddd) B is phenyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro and trifluoromethyl
  • (eeeee) B is isoxazolyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy;
  • (fffff) B is isoxazolyl; m is 1 or 2;
  • R 6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (ggggg) B is pyrazolyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy;
  • (hhhhh) B is pyrazolyl; m is 1 or 2;
  • R 6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl);
  • (iiiii) B is thiadiazolyl; m is 1 or 2; and R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy and butoxy;
  • (jjjj) B is thiadiazolyl; m is 1 or 2; and R 6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (
  • R 1 and R 2 are both hydrogen, R 3 and R 4 are both hydrogen, n is 0, L is -NHC(O)NH-, and ring B-R 6 , where m is 1 or 2, is selected from 3-acetylaminophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl,, 3,4-dichloro-phenyl, 2-morpholin-4-ylphenyl, 5-tert-butyl- 1 ,3,4-thiadiazol-2-yl, 3-methylisothiazol-5-yl, 3-methylisoxazol-5-yl, 5-tert-butylisoxazol-3 -yl, 1 -methyl-3 -tert-butyl-pyrazol-5-yl, 1 -methylpiperidin-4-
  • R y is a group NR 1 R 2
  • R x is a group R 3a and R z is a group R 4a and R 3a and R 4a are hydrogen
  • ring A is phenyl or pyridyl
  • n is 0 or 1
  • R 5 is methyl
  • L is -NHC(O)NH-CH 2 -
  • ring B-R 6 is selected from 2-chloro-phenyl, 2-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3 -methoxy -phenyl, 2-methylamino ⁇ henyl, 2-morpholin ⁇ 4-ylphenyl, or 2-piperin- 1 -ylphenyl.
  • A is selected from phenyl or pyridyl; B is selected from isoxazolyl or pyrazolyl; D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; and R 1 , R 2 , R 3 , R 5 , R 6 , L, n, m and p are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof.
  • L is a group -C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - or
  • A is other than pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and in particular A is phenyl.
  • x is greater than 0 and/or Z is other than a direct bond.
  • a compound of the Formula I, or a pharmaceutically acceptable salt thereof may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a novel compound of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • a process for preparing a compound of formula IC or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , L , ring A, ring B, ring D, n, m and p are, unless otherwise specified, as defined in formula I) as described schematically below.
  • R 1 , R 5 , R 8 , n, p, D and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an isocyanate of the formula III:
  • R , R a , R , x, y m, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
  • Ar is a suitable aryl group, for example phenyl
  • Z, R 6 , R a , R b , x, y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
  • W is -C(R a R b )- or a direct bond and R 1 , R 5 , R 8 , R a , R b , n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a heterocycle of the formula VI:
  • Vl wherein Lg 2 is a suitable displaceable group, for example halogeno (such as chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy , and Z, R 6 , R a , R b , m, x, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (d) For compounds of the formula IC wherein L is a suitable displaceable group, for example halogeno (such as chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy , and Z, R 6 , R a , R b , m, x, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (d) For compounds of the formula IC wherein L is halogeno (such as chloro, bromo), O-tosyl, O
  • Ar is a suitable aryl group, for example phenyl
  • R 1 , R 5 , n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula IX as defined above.
  • Lg 1 is a suitable displaceable group, for example halogeno (such as fluoro, chloro or bromo) and R 6 , m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
  • R 6 , R a , R b , x, y m, Z and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary and wherein Lg 1 is a suitable displaceable group for example halogeno (such as fluoro, chloro or bromo); or
  • Lg 1 is a suitable displaceable group, for example halogeno (such as fluoro, chloro, bromo), O-tosyl, O-mesyl or ⁇ rifluorosulphonyloxy and R 6 , R a , R b , y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
  • halogeno such as fluoro, chloro, bromo
  • R 6 , R a , R b , y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
  • Y is -S(O) 2 N(R 8 )- or -N(R 8 )S(O) 2 - and Lg 2 is a suitable displaceable group, as described above and R 1 , R 5 , R 8 , R a , R b , n, p, x, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of formula XXI,
  • Lg 3 is a suitable displaceable group for example halogeno (such as fluoro, chloro, bromo or iodo), methylsulfonyl, methylsulphinyl methylthio or aryloxy (such as phenoxy) and R 1 , R 5 , R 6 , n, m, p, A, B, D and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR 2 R 3 , wherein R 2 and R 3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (n) The reaction of a compound of the formula XXIII:
  • Lg 4 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifmoromethylsulfonyloxy) and R 5 , R 6 , n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an heterocyle of the formula XXIV:
  • Lg 5 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifluoromethylsulfonyloxy) and R 1 , p and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary; and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt or solvate.
  • reaction of process (a) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an amine such as pyridine or a dipolar aprotic solvent such asJ ⁇ ,N-dimethylformamide or N,N-dimethylacetamide.
  • a suitable inert solvent or diluent for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an amine such as pyridine or a dipolar aprotic solvent such asJ ⁇ ,N-dimethylformamide or N,N-dimethylacetamide.
  • a suitable inert solvent or diluent for example a
  • the reaction of process (b) is conveniently carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine).
  • the reaction of process (b) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 120 0 C, preferably from about 80°C to about 100 0 C.
  • this reaction may also be performed by heating the reactants in a sealed vessel using a suitable heating apparatus such as a microwave heater.
  • a suitable heating apparatus such as a microwave heater.
  • a suitable coupling agent is, for example, a suitable peptide coupling agent, for example O-(7-azabenzotriazol-l-yl) ⁇ N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or a suitable carbodiimide such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole (CDI), optionally in the presence of a catalyst such as dimethylaminopyridine or hydroxybenzotriazole.
  • the reaction of process (d) may conveniently be carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
  • Another suitable base is, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, caesium carbonate or calcium carbonate.
  • the reaction of process (c) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
  • a suitable inert solvent or diluent for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene or a
  • a suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate, such as sodium carbonate, potassium carbonate, caesium carbonate or calcium carbonate.
  • reaction of process (d) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,
  • N-methylpyrrolidin-2-one or dimethylsulfoxide is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 12O 0 C, preferably from about 100 0 C to about 120 0 C.
  • this reaction may also be performed by heating the reactants in a sealed vessel using a suitable heating apparatus such as a microwave heater.
  • reaction of process (e) is conveniently carried out under the conditions as described above for process (a).
  • reaction of process (f) is conveniently carried out under the conditions as described above for process (b).
  • the reaction of process (h) is conveniently carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
  • the reaction of process (h) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride or an ether such as tetrahydrofuran or 1,4-dioxane.
  • the reaction is conveniently carried out at a temperature in the range, for example, from about - 10 0 C to about 3O 0 C, preferably at or near 0 0 C.
  • reaction of process (i) is conveniently carried out in the presence of a suitable solvent or diluent, such as methylene chloride, THF or pyridine, in the presence of a base such as triethylamine or pyridine.
  • a suitable solvent or diluent such as methylene chloride, THF or pyridine
  • a base such as triethylamine or pyridine.
  • the reaction is conveniently carried at a temperature between ambient temperature and 100 0 C.
  • reaction of process (j) is conveniently carried out under the conditions as described above for process (i).
  • Reaction Conditions for Process (k) The reaction of process (k) is conveniently carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
  • reaction of process (k) is conveniently carried out in the presence of a suitable solvent or diluent, for example tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide.
  • a suitable solvent or diluent for example tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide.
  • the reaction is conveniently carried out at a temperature in the range, for example, from about ambient temperature to about 100 0 C, and under atmospheric pressure.
  • Reaction Conditions for Process (1) The reaction of process (1) is conveniently carried out under the conditions as described above for process (k).
  • the reaction of process (m) may be carried out in the presence of a catalytic amount of a suitable acid.
  • a suitable acid is, for example, hydrogen chloride
  • the reaction of process (m) may conveniently be carried out in the absence or the presence of a suitable inert solvent or diluent.
  • a suitable inert solvent or diluent when used, is for example an alcohol such as ethanol, isopropanol or butanol or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 12O 0 C, preferably from about ambient temperature to about 60 0 C.
  • the reaction of process (n) is conveniently carried out in the presence of a suitable palladium catalyst, optionally in combination with a suitable copper catalyst.
  • a suitable palladium catalyst is, for example, bis(triphenylphosphine)palladium dichloride, [1,1'- bis(diphenylphosphino)ferrocene] palladium dichloride or tetrakis(triphenylphosphine)palladium(0).
  • a suitable copper catalyst is, for example, copper (I) iodide.
  • the reaction of process (n) is conveniently carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base, such as a trialkylamine (for example triethylamine) or tetramethylguanidine.
  • the reaction of process (n) may conveniently be carried out in the absence or presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
  • the reaction is conveniently carried out at a temperature in the range, for example, from about -20 0 C to about 100 0 C.
  • Reaction Scheme 1 wherein Lg 4 is a suitable displaceable group as described above and R 1 , R 5 , R 8 , n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • reaction of Reaction Scheme 1 is conveniently carried out under the conditions as described above for process (n).
  • compounds of the formula II may be obtained by reaction of a pyrimidine of the formula XXVII with a protected alkyne of the formula XXIX and then with an amine of the formula XXX as illustrated in Reaction Scheme 2:
  • Reaction Scheme 2 wherein Lg 4 in the compounds of the formulae XXVII and XXX are each a suitable displaceable group as described above, Pg is a suitable protecting group, for example a trialkylsilyl group, such as trimethylsilyl or tert-butyldimethylsilyl or Me 2 (OH)C- and R 1 , R 5 , R 8 , n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • Pg is a suitable protecting group, for example a trialkylsilyl group, such as trimethylsilyl or tert-butyldimethylsilyl or Me 2 (OH)C- and R 1 , R 5 , R 8 , n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • Step (i) of Reaction Scheme 2 is the coupling of a protected alkyne of the formula XXIX to a heterocycle of the formula XXVII. Step (i) is carried out under conditions as described above for process (n).
  • Reaction Scheme 2 is the deprotection of the alkyne under basic or acidic conditions to provide an unsubstituted alkyne. A person skilled in the art would readily be able to select the appropriate conditions for deprotection in step (ii).
  • Step (iii) of Reaction Scheme 2 is the coupling of the alkyne to an amine of the formula XXX. Step (iii) of Reaction Scheme 2 is carried out under conditions as described above for process (o).
  • compounds of the formula II may be obtained by reaction of a compound of the formula XXXI, wherein R 1 , R 5 , R 8 , n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR 2 R 3 wherein R 1 and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary ,using reaction conditions as described above for process (n).
  • the starting materials of the formulae XXVII, XXVIII, XXIX, XXX and XXXI and the amine HNR 2 R 3 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
  • Isocyanates of the formula III are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
  • the isocyanates can conveniently be prepared from the corresponding acids or acid chlorides via a Curtis reaction with for example azide or diphenylphosphoryl azide.
  • the isocyanates can conveniently be prepared by reaction of the corresponding amine with phosgene or a phosgene equivalent, for example triphosgene, diphosgene or N,N'-carbonyldiimidazole (March J., Adv. Org. Chem., 4 th edition, 1992, page 1290, Wiley Interscience).
  • phosgene or a phosgene equivalent for example triphosgene, diphosgene or N,N'-carbonyldiimidazole
  • Aryl carbamates of the formula IV are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
  • the aryl carbamates can be prepared by reaction of an amine of the formula XXXII with an arylchloroformate as illustrated in Reaction Scheme 3:
  • Reaction Scheme 3 wherein R 6 , R a , R b , m, x, y, B, Z and Ar have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • the reaction of Reaction Scheme 3 is conveniently carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine).
  • the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane.
  • a suitable inert solvent or diluent for example an ether such as tetrahydrofuran or 1,4-dioxane.
  • the reaction is conveniently carried out at a temperature in the range, for example, from about -20°C to about 100 0 C, preferably at or near 0 0 C.
  • Trichloroacetylamines of the formula VII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (e)
  • isocyanates of the formula VIII can conveniently be prepared from the corresponding acids or acid chlorides via a Curtis reaction for example with azide or diphenylphosphoryl azide.
  • the isocyanates can conveniently be prepared by reaction of the corresponding amine with phosgene or a phosgene equivalent, for example triphosgene, diphosgene or N,N'- carbonyldiimidazole (March J., Adv. Org. Chem., 4 th edition, 1992, page 1290, Wiley Interscience).
  • the activated sulphonyls can conveniently be prepared from the corresponding sulphonic acids by reaction with phosphorous oxy chloride or thionyl chloride by heating under reflux.
  • compounds of the formula XXII can be prepared using similar processes to those described above using the appropriate starting materials, for example, wherein the starting materials carry an, optionally protected, group Lg 3 in place of the -NR 2 R 3 group.
  • Amines of the formula HNR 2 R 3 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
  • Starting Materials for Process (n) Compounds of formula XXIII are commercially available or they are known in the literature, or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials.
  • compounds of the formula XXIII wherein L is -N(R 8 )S(O) 2 -(CR a R b ) x -Z-(CR a R b ) y - may conveniently be obtained by reaction of an amine of the formula XXXIII with an activated sulphonyl of the formula XXXIV (as described above) as illustrated in Reaction Scheme 4: XXXIl!
  • Lg 4 is a suitable displaceable group as described above, L is -N(R 8 )S(O) 2 -(CR a R b ) ⁇ -Z-(CR a R b ) y - and R 5 , R 6 , R 8 , R a , R b , n, m, x, y, A, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • reaction of Reaction Scheme 4 is conveniently carried out under the conditions as described above for process (a).
  • Alkynes of the formula XXIV are commercially available or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials.
  • compounds of the formula XXIV may conveniently be obtained by reaction of a heterocycle of the formula XXXIV:
  • Examples of the types of conversion reactions that may be used include introduction of a substiruent by means of an aromatic substitution reaction or of a nucleophilic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under
  • nucleophilic substitution reactions include the introduction of an alkoxy group or of a monoalkylamino group, a dialkyamino group or a N-containing heterocycle using standard conditions.
  • reduction reactions include the reduction of a carbonyl group to a hydroxy group with sodium borohydride or of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating.
  • An example of a suitable conversion reaction is the conversion of a carbamate compound of the formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , n and A are as defined in claim 1, L is N(H)C(O)-O-, B is an optionally substituted phenyl group, to a compound of the formula I wherein L is N(H)C(O)NH and R 1 , R 2 , R 3 , R 4 , R 5 , n, B and A are as defined in claim 1.
  • Such a conversion may be achieved using standard procedures, for example by reaction of the carbamate with an appropriate amine, for example under conditions as described above for process (b).
  • Another example of a suitable conversion reaction is the conversion of a compound of the formula I wherein R 2 , R 3 , R 4 , R 5 , R 6 , n, m, A, B and L are as defined in claim 1 and R 1 and/or R 2 is hydrogen to a compound of the formula I wherein R 1 and/or R 2 is, for example, an optionally substituted (l-6C)alkoxycarbonyl group.
  • R 1 and/or R 2 is, for example, an optionally substituted (l-6C)alkoxycarbonyl group.
  • Such a conversion may be achieved using standard procedures, for example by substitution of one or both of the hydrogen atoms R 1 and/or R 2 for a desired, optionally substituted, (l-6C)alkoxycarbonyl group.
  • Certain compounds of Formula I are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula I and mixtures thereof including racemates. Tautomers and mixtures thereof also
  • Isomers may be resolved or separated by conventional techniques, e.g. chromatography or fractional crystallisation.
  • Enantiomers may be isolated by separation of aracemic or other mixture of the compounds using conventional techniques (e.g. chiral High Performance Liquid Chromatography (HPLC)).
  • HPLC High Performance Liquid Chromatography
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) or may be made with achiral starting materials and chiral reagents. All stereoisomers are included within the scope of the invention.
  • the compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
  • the following assays can be used to measure the effects of the compounds of the present invention as Tie2 inhibitors in vitro and as inhibitors of Tie2 autophosphorylation in whole cells. a. In vitro receptor tyrosine kinase inhibition assay
  • compounds are evaluated in a non-cell based protein kinase assay by their ability to inhibit the protein kinase enzyme phosphorylation of a tyrosine containing polypeptide substrate in an ELISA based microtitre plate assay.
  • the assay was to determine the IC 50 , for three different recombinant human tyrosine kinases Tie2, KDR and Fit.
  • recombinant receptor genes were produced using standard molecular biology cloning and mutagenesis techniques. These recombinant proteins fragments encoded within these genes consist of only the intracellular portion C-terminal portion of the respective receptor, within which is found the kinase domain.
  • the recombinant genes encoding the kinase domain containing fragments were cloned and expressed in standard baculovirus/Sf21 system (or alternative equivalent).
  • Lysates were prepared from the host insect cells following protein expression by treatment with ice-cold lysis buffer (2OmM N-2-hydroxyethylpiperizine- N'-2-ethanesulphonic acid (HEPES) pH7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl 2 , 1 mM ethylene glycol-bis ( ⁇ -aminoethyl ether) N',N',N',N'- tetraacetic acid (EGTA), plus protease inhibitors and then cleared by centrifugation. Tie2, KDR and Fltl lysates were stored in aliquots at -80 0 C.
  • Constitutive kinase activity of these recombinant proteins was determined by their ability to phosphorylate a synthetic peptide (made up of a random co-polymer of Glutamic Acid, Alanine and Tyrosine in the ratio of 6:3:1). Specifically, Nunc MaxisorbTM 96-well immunoplates were coated with 100 microlitres of synthetic peptide Sigma P3899 (lmg/ml stock solution in PBS diluted 1:500 in PBS prior to plate coating) and incubated at 4 0 C overnight. Plates were washed in 50 mM HEPES pH 7.4 at room temperature to remove any excess unbound synthetic peptide.
  • KDR or Fltl activities were assessed by incubation of the appropriate freshly diluted lysates (1:200, 1:400 and 1:1000 respectively) in peptide coated plates for 60 minutes (Tie2) or 20 minutes for (KDR, Fit) at room temperature in 100 niM HEPES pH 7.4 , adenosine trisphosphate (ATP) at 5 micromolar (or Km concentration for the respective enzyme, 10 mM MnCl 2 , 0.1 mM Na 3 VO 4 , 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100 together with the test com ⁇ ound(s) in dissolved in DMSO (final
  • the immobilised phospho-peptide product of the reaction was detected by o immunological methods. Firstly, plates were incubated for 4 hours at room temperature with murine monoclonal anti-phosphotyrosin -HRP (Horseradish Peroxidase) conjugated antibodies (4G10 from Upstate Biotechnology UBI 16-105).
  • murine monoclonal anti-phosphotyrosin -HRP Haseradish Peroxidase conjugated antibodies
  • HRP activity in each well of the plate was measured colorimetrically using 22'-Azino-di-[3-ethylbenzthiazoline sulfonate (6)] diammonium salt crystals ABTS 5 (Sigma P4922 - prepared as per manufactures instructions) as a substrate incubated for 30- 45 minutes to allow colour development, before lOOul of IM H2SO4 was added to stop the reaction.
  • This assay is based on measuring the ability of compounds to inhibit autophosphorylation of the Tie2 receptor which normally leads to the production of "activated" receptor that in turn initiates the particular signal transduction pathways associated with the receptor function.
  • Autophosphorylation can be achieved by a number of means. It is known that expression of recombinant kinase domains in baculoviral systems can lead to the production of phosphorylated and activated receptor. It is also reported that over expression of receptors in recombinant cell lines can itself lead to receptor autophosphorylation in the absence of the ligand (Heldin C-H. 1995 Cell : 80, 213-223; Blume-J. P, Hunter T. 2001 Nature: 411, 355-65).
  • chimaeric receptors have been constructed.
  • the natural, external cell surface domain of the receptor has been replaced with that of a domain which is known to be readily dimerised via the addition of the appropriate ligand (e.g. TrkA-Tie2/NGF ligand (Marron, M.B., et al., 2000 Journal of Biological Chemistry : 275:39741-39746) or C-fms-Tie-1/CSF-l ligand (Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713).
  • TrkA-Tie2/NGF ligand Marron, M.B., et al., 2000 Journal of Biological Chemistry : 275:39741-39746
  • C-fms-Tie-1/CSF-l ligand Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713.
  • ligand Naturally if the ligand is available one can use natural cell lines or primary cells which are known to express the receptor of choice and simply stimulate with ligand to achieve ligand induced phosphorylation.
  • the ability of compounds to inhibit autophosphorylation of the Tie2 receptor which is expressed for example in EA.hy926/B3 cells (supplied by J. McLean/ B. Tuchi, Univ.of N. Carolina at Chapel Hill, CB- 4100, 300 Bynum Hall, Chapel Hill, N.C. 27599-41000, USA) or primary HUVEC (human umbilical vein endothelial cells - available from various commercial sources), can measured by this assay.
  • Natural Angl ligand can be isolated using standard purification technology from either tumour cell supernatants or alternatively the Angl gene can be cloned and expressed recombinantly using stand molecular biology techniques and expression systems. In this case one can either attempt to produce the ligand either in its native state or as recombinant protein which for example may have been genetically engineered to contain additional of purification tags (eg. polyhistidine peptides, antibody Fc domains) to facilitate the process.
  • purification tags eg. polyhistidine peptides, antibody Fc domains
  • EA.hy926/B3 or HUVEC cellular Tie2 receptor a Angl ligand stimulated cellular receptor phosphorylation assay can be constructed which can be used to analyse to determine the potential of compounds to inhibit this process.
  • EA.hy926/B3 cells were grown in the appropriate tissue culture media plus 10% foetal calf serum (FCS) for two days in 6 well plates starting with an initial seeding density of 5x10 5 cells/well. On the third day the cells were serum starved for a total of 2 hours by replacing the previous media with media containing only 1% FCS.
  • FCS foetal calf serum
  • the ligand plus orthovandiate was added to stimulate autophosphorylation of the cellular Tie2 receptor (ligand can be added either as purified material diluted in serum starvation media or non-purified cell supernatant containing ligand e.g. when recombinantly expressed mammalian cells).
  • the cells were cooled on ice washed with approximately 5mls with cold PBS containing 1 mM orthovanadate, after which 1 ml of ice cold lysis buffer ((20 mM Tris pH 7.6, 150 mM NaCl, 50 mM NaF, 0.1 % SDS, 1% NP40, 0.5 % DOC, 1 mM orthovanadate, 1 mM EDTA, 1 mM PMSF, 30 ⁇ l / ml
  • the beads were removed by exposing the tubes for 1 minutes in the magnet, and the total liquid separated from the beads from each immuno-precipitate loaded onto Polyacrylamide/SDS protein gels (pre-cast 4-12 % BisTris NuPAGE / MOPS 12 well gels from Novex). Protein gels were run at 200 V and then blotted onto NC membrane for
  • the antibody was left on for 1 hour at room temperature before subsequently washing the blots with PBS-Tween.
  • the western blots of the various immuno-precipitated samples were developed the blots with LumiGLO (NEB 7003). And transferred to an X-Ray cassette and films exposed for 15 sec / 30 sec and 60 sec.
  • the relative strength of the protein band which pertains to the phosphorylated Tie2 receptor was evaluated using a FluorS BioRad image analyser system. The percentage phosphorylation for each test compound dilution series was determined from which IC50 values were calculated by standard methods using the appropriate control samples as reference.
  • Table A illustrates the activity of representative compounds according to the invention.
  • Column 2 of Table A shows IC 50 data from Test (a) for the inhibition of Tie2 receptor tyrosine kinase in vitro and column 3 shows IC 50 data from Test (b) for the inhibition of autophosphorylation of Tie2 receptor tyrosine kinase.
  • a pharmaceutical composition which comprises a compound of the Formula IC, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the compounds according to the present invention as defined herein are of interest for, amongst other things, their antiangiogenic effect.
  • the compounds of the invention are expected to be useful in the treatment or prophylaxis of a wide range of disease states associated with undesirable or pathological angiogenesis, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • Cancer may affect any tissue and includes leukaemia, multiple myeloma and lymphoma.
  • compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
  • the compounds of the present invention are expected be useful to produce a Tie2 inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention may be used to produce an antiangiogenic effect mediated alone or in part by the inhibition of Tie2 receptor tyrosine kinase.
  • the compounds of the invention are expected to inhibit any form of cancer associated with Tie2. For example, the growth of those primary and recurrent solid tumours which are associated with Tie2, especially those tumours which are significantly dependent on Tie2 receptor tyrosine kinase for their growth and spread.
  • Formula IC or a pharmaceutically-acceptable salt thereof, as defined hereinbefore, for use as a medicament.
  • a compound of the formula I (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of an anti-angiogenic effect in a warm-blooded animal such as man.
  • a compound of the formula I (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancers in a warm-blooded animal such as man.
  • a compound of the formula I (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid and skin cancer in a warm-blooded animal such as man.
  • a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid and skin cancer in a warm-blooded animal such as man.
  • a method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating cancers in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a compound of the formula I such as a compound of formula IC
  • a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man.
  • a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in producing an anti-angiogenic effect in a warm-blooded animal, such as man.
  • a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of cancer.
  • a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid or skin cancer.
  • a compound of the present invention will possess activity against other diseases mediated by undesirable or pathological angiogenesis including psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • the anti-angiogenic activity defined herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734 such as
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitor
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytoldne-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a pharmaceutical product comprising a compound of the Formula I as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of Formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0 C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates;
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSOd 6 ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;
  • DMTMM 4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4-methyhnorpholin-4-ium chloride dppf 1 , 1 ' -Bis(diphenylphosphino)ferrocene
  • Phenyl (5-tert-butylisoxazol-3-yl)carbamate (160 nig) was added to a stirred solution of [3-(pyrimidin-5-ylethynyl)phenyl]amine (Intermediate 1) (100 mg) and triethylamine (0.086 mL) in THF (10 niL). The reaction mixture was heated at 75°C for 4 hours. The solvent was evaporated and the residue triturated with ether (20 mL) and the resultant solid was purified by flash chromatography on silica using 0-10% MeOH in DCM as eluent. The resultant product was triturated with ether (20 mL) to give the title compound as a colourless solid (120 mg, 65%);
  • Phenyl chloroformate (52 mL) was added dropwise to a solution of 3-amino-5-tert- butylisoxazole (52.3 g) in THF (1.0 L) and pyridine (60 mL) at O 0 C. When the addition was complete water (500 mL) was added and the reaction mixture stirred for 45 mins while warming to ambient temperature, before extracting into ether (3 x 300 ml). The combined organics were washed with water, brine and concentrated in vacuo, azeotroping with toluene and chloroform to give the title compound as a colourless solid (96.3 g, 99%).

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Abstract

The invention relates to a compound of the Formula (I) I or salt, prodrug or solvate thereof, wherein R1, R5, R6, D, A, B, L, n, m and p are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.

Description

Compounds
This invention relates to compounds, or pharmaceutically acceptable salts thereof, which possess anti-angiogenic activity and are accordingly useful in methods of treatment of disease states associated with angiogenesis in the animal or human body. The invention also concerns processes for the preparation of the compounds, pharmaceutical compositions containing the compounds as active ingredient, and methods for the use of the compounds in the manufacture of medicaments for use in the production of anti- angiogenic effects in warm-blooded animals such as humans. The Tie2 receptor tyrosine kinase (also known as TEK) is expressed predominantly in endothelial and haematopoietic cells and is essential for vessel formation and maintenance (Jones, N. et al. Nature Reviews Molecular Cell Biology. 2001: 2, 257-67).
Angiogenesis is a fundamental process defined as the generation of new blood vessels from existing vasculature. It is a vital yet complex biological process required for the formation and physiological functions of virtually all the organs. Normally it is transient in nature and is controlled by the local balance of angiogenic and angiostatic factors in a multi-step process involving vessel sprouting, branching and tubule formation by endothelial cells (involving processes such as activation of endothelial cells (ECs), vessel destabilisation, synthesis and release of degradative enzymes, EC migration, EC proliferation, EC organisation and differentiation and vessel maturation).
Normal angiogenesis plays an important role in a variety of processes and is under stringent control. In the adult, physiological angiogenesis is largely confined to wound healing and several components of female reproductive function and embryonic development. In undesirable or pathological angiogenesis, the local balance between angiogenic and angiostatic factors is dysregulated leading to inappropriate and/or structurally abnormal blood vessel formation. Pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacology. Science. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). In cancer, growth of primary and secondary tumours beyond 1-2 mm3 requires angiogenesis (Folkman, J. New England Journal of Medicine 1995; 33, 1757-1763). In diseases such as cancer in which progression is dependant on aberrant angiogenesis, blocking the process can lead to prevention of disease advancement (Folkman, J. 1995, Nature Medicine. 1: 27-31). Many factors are described in the scientific literature that are believed to play important critical roles in the regulation of angiogenesis. Two major classes of angiogenic factors are the vascular endothelial growth factor (VEGF) and the angiopoietins. These polypeptide moieties interact with their respective receptors (transmembrane tyrosine kinases which are predominantly endothelial cell specific) and induce cellular responses via ligand mediated signal transduction. It has been speculated that VEGF and the angiopoietins co-operate to regulate various aspects of the angiogenic process during both normal and pathological angiogenesis via signalling through their respective receptors.
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Fit or Fltl, the kinase insert domain-containing receptor, KDR (also referred to as FIk-I), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fit and KDR, have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
Recently a second family of predominantly endothelial cell specific receptors that regulate vessel destabilisation and maturation have been identified. The Tie receptors and their ligands, the angiopoietins, co-operate closely with VEGF during both normal and pathological angiogenesis. The transmembrane receptors Tiel and Tie2, constitute a family of endothelial cell specific tyrosine kinase receptors involved in maintenance of blood vessel integrity and which are involved in angiogenic outgrowth and vessel remodelling. Structurally Tiel and Tie2 share a number of features (e.g. the intracellular domains of both these receptors each contain a tyrosine kinase domain interrupted by a kinase insert region) and thus constitute a distinct RTK subfamily. Overall sequence identity between Tiel and Tie2 receptors at the amino acid level is 44% while their intracellular domains exhibit 76% homology. Targeted disruption of the Tiel gene results in a lethal phenotype characterised by extensive haemorrhage and poor microvessel integrity (Puri, M. et al. 1995 EMBO Journal: 14:5884-5891). Transgenic mice deficient in Tie2 display defects in vessel sprouting and remodelling and display a lethal phenotype in mid gestation (E9.5- 10.5) caused by severe defects in embryonic vasculature (Sato, T. et al. 1995 Nature 370: 70-74).
To date no ligands have been identified for Tiel and little is known regarding its signalling abilities. However, Tiel is believed to influence Tie2 signalling via heterodimerisation with the Tie2 receptor hence potentially modulating the ability of Tie2 to autophosphorylate (Marron, M. et al. 2000 Journal of Biological Chemistry: 275, 39741- 39746) and recent chimaeric Tiel receptor studies have indicated that Tie-1 may inhibit apoptosis via the PI 3 kinase/Akt signal transduction pathway (Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713). In contrast, a number of ligands, designated the angiopoietins have been identified for Tie2 of which Angiopoietin 1 (Angl) is the best characterised. Binding of Angl induces tyrosine phosphorylation of the Tie2 receptor via autophosphorylation and subsequently activation of its signalling pathways via signal transduction. Ang2 has been reported to antagonise these effects in endothelial cells (Maisonpierre, P. et al. 1997 Science: 277, 55-60). The knock-out and transgenic manipulation of Tie2 and its ligands suggest that stringent spatial and temporal control of Tie2 signalling is imperative for the correct development of new vasculature. There are also reports of at least another two ligands (Ang3 and Ang4) as well as the possibility of heterodimerisation between the angiopoietin ligands that has the potential to modify their activity (agonistic/antagonistic) on association with the receptor. Activation of the Tie2 receptor by Angl inhibits apoptosis (Papapetropoulos, A., et al., 2000 Journal of Biological Chemistry : 275 9102-9105), promotes sprouting in vascular endothelial cells (Witzenbicher, B., et al., 1998 Journal of Biological Chemistry: 273, 18514-18521) and in vivo promotes blood vessel maturation during angiogenesis and reduces the permeability and consequent leakage from adult microvessels (Thurston, G. et al., 2000 Nature Medicine: 6, 460-463). Thus activated Tie2 receptor is reported to be involved in the branching, sprouting and outgrowth of new vessels and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and overall appears to be consistent with promoting microvessel stability. Absence of Tie2 activation or inhibition of Tie2 auto phosphorylation may lead to a loss of vascular structure and matrix/cell contacts (Thurston, G., Cell Tissue Res (2003), 314: 61-69) and in turn may trigger endothelial cell death, especially in the absence of survival or growth stimuli. On the basis of the above reported effects due to Tie2 kinase activity, inhibiting Tie2 kinase may provide an anti-angiogenic effect and thus have application in the therapy of disease states associated with pathological angiogenesis. Tie2 expression has been shown to be up- regulated in the neovasculature of a variety of tumours (e.g. Peters, K.G. et al, British Journal of Cancer 1998; 77,51-56) suggesting that inhibiting Tie2 kinase activity will result in anti-angiogenic activity. In support of this hypothesis, studies with soluble Tie2 receptor (extracellular domain) (Pengnian, L. et al., 1997, Journal of Clinical Investigation 1997: 100, 2072-2078 and Pengnian, L. et al., 1998, Proceedings of the National Academy of Sciences 1998: 95, 8829-8834) have shown anti-tumour activity in in vivo tumour models. In addition these experiments also indicate that disruption of the Tie2 signalling pathways in a normal healthy individual may be well tolerated as no adverse toxicities were observed in these studies.
Examination of human primary breast cancer samples and human and murine breast cancer cell lines (Stratmann, A., et al., 2001, International Journal of Cancer: 91,273-282) indicate that Tie2 dependant pathways of tumour angiogenesis may exist alongside KDR dependant pathways and, in fact, may operate both independently (Siemeister G., et al., 1999 Cancer Research: 59, 3185-3191) as well as in concert with each other (e.g. VEGF A and Angl reported to collaborate to induce angiogenesis and produce non-leaky mature vessels Thurston, G, et al., 1999 Science: 286, 2511-2514). It is quite possible that a mix of such angiogenic processes even exist within a single tumour. Tie2 has also been shown to play a role in the vascular abnormality called venous malformation (VM) (Mulliken, J.B. & Young, A.E. 1998, Vascular Birthmarks: W. B. Saunders, Philadelphia). Such defects can either be inherited or can arise sporadically. VM's are commonly found in the skin or mucosal membranes but can affect any organ. Typically lesions appear as spongy, blue to purple vascular masses composed of numerous dilated vascular channels lined by endothelial cells. Among the inherited forms of this disease the most common defect appears to be a Tie2 kinase mutation C2545T in the Tie2 coding sequence (Calvert, J.T., et al., 1999 Human Molecular genetics: 8, 1279-1289), which produces a R849W amino acid substitution in the kinase domain. Analysis of this Tie2 mutant indicates that it is constitutively activated even in the absence of ligand (Vikkula, M., et al, 1996 Cell: 87, 1181-1190).
Upregulation of Tie2 expression has also been found within the vascular synovial pannus of arthritic joints in humans, which is consistent with the role of inappropriate neovascularisation.
Such examples provide further indications that inhibition of Tie2 phosphorylation and subsequent signal transduction will be useful in treating disorders and other occurrences of inappropriate neovascularisation. To date only a few inhibitors of Tie2 are known in the art. For example, Internation Application No: WO 04/013141 describes a group of condensed pyridines and pyrimidines and International Application No: WO 04/058776 describes a group of pryidine and pyrimidine compounds. There is thus a need to identify additional Tie2 inhibitors that could exploit the full therapeutic potential of inhibiting/ modulating the Tie2 signalling pathways.
We have found that certain compounds possess inhibitory activity for the Tie2 receptor tyrosine kinase and accordingly have value in the treatment of disease states associated with pathological angiogenesis such as cancer, rheumatoid arthritis, and other diseases where active angiogenesis is undesirable.
According to a first aspect of the present invention there is provided the use of a compound of the Formula I:
Figure imgf000007_0001
Formula I wherein: A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
B represents a (3-7C)cycloallcyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur and which is saturated, partially saturated or aromatic;
D represents 5 or 6 membered nitrogen-containing heteroaryl ring which optionally comprises 1 or 2 or 3 further heteroatoms independently selected from oxygen, nitrogen or sulphur;
L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(RaRb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(RaRb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)r, -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or -S(O)2N(R9)-(CRaRb)x-Z-(CRaRb)y-, -N(R8)C(O)-O-(CRaRb)x-Z-(CRaRb)y- or -O-C(O)-N(R9)-(CRaRb)x-Z-(CRaRb)r; wherein Z is a direct bond, -O- or -N(R8)- wherein x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4 and where L is a group -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- where Z is a group -N(R8)-, then x is other than 0, wherein R8 and R9 represents hydrogen or (l-6C)alkyl, wherein Ra and Rb independently represent hydrogen or (l-6C)alkyl or Ra and Rb together with the carbon atom to which they are attached represent (3-6C)cycloalkyl; and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
R1 is selected from hydrogen, hydroxy, (l-6C)alkyl, (l-6C)alkoxy or (3-7C)cycloalkyl wherein the (l~6C)alkyl, (l-6C)alkoxy and the (3-7C)cycloalkyl groups are optionally substituted by one or more groups independently selected from halo, hydroxy, (l-6C)alkyl, (l-βC)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or R1 represents a group -NR2R3 as defined below;
p is 0, 1, 2 or 3;
R2 and R3 are independently selected from hydrogen, (l-βC)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6 , or a 5 or 6 membered heteroaryl ring, or R2 and R3 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein a (l-6C)alkyl, the (l-6C)alkoxy, the (l-6C)alkanoyl and the (3- 6C)cycloalkyl groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or -N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (l-6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, mono(l-6C)alkylcarbamoyl, di- [(I -6C)alkyl] carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more hydroxy groups; wherein the phenyl is optionally substituted by one or more groups independently selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, wherein the (l-6C)alkyl and (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more of the following: (l-4C)alkyl, (1- 4C)alkoxy, (l-4C)alkoxy(l-4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-[(l- 6C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)zR4 wherein z is 0, 1, 2 or 3 and R4 is selected from hydrogen, hydroxy, (1- 4C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy;
R5 is selected from cyclopropyl, cyano, halo, (l-6C)alkoxy or (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or by one or more fluoro;
n is 0, 1, 2 or 3;
R6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, -S(O)q-(l-6C)alkyl wherein q is 0, 1 or 2, -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl,
-S(O)q-(l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl]amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl or hydroxy(l-6C)alkyl; and m is 0, 1, 2 or 3;
and when B is a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10 membered bicyclic group, the rings and bicyclic group optionally bear 1 or 2 oxo or thioxo substituents; and salts or solvates thereof. with the proviso that:
(i) when D is pyrimidin-5-yl, the 4-position of the pyrimidin-5-yl is substituted by R1, the 6-position of the pyrimidin-5-yl is substituted by -NR2R3, and L is
-C(RaRb)C(O)N(R9>, -N(R8)C(O)C(RaRb)-, -N(R8)C(O)N(R9)-, -N(R8)C(O)O-, or -OC(O)-N(R9)- and a (l-6C)alkyl group in Ra or Rb is unsubstituted then the 2- position of the pyrimidin-5-yl cannot be substituted by hydrogen, (l-6C)alkyl or (1- 6C)alkoxy; (ii) when L represents -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or
-S(O)2N(R8)-(CRaRb)x-Z-(CRaRb)y-, where x+y > 0, D is pyrimidin-5-yl, and one of R1 is a group NR2R3, then p is 3 and the other two R1 groups are also NR2R3 groups;
(iii) when L is -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- where x + y>0, D is pyrimidin-5- yl and one of R1 is a group NR2R3, then p is 3 and the other two R1 groups are also NR2R3 groups;
(iv) where L represents -C(RaRb)C(O)N(R9)-, -N(R8)C(O)C(RaRb)-, -N(R8)C(O)N(R9)-,
-N(R8)C(O)O-, or -OC(O)-N(R9)-, D is pyrimidin-5-yl, and the 2-position of the pyrimidinyl-5-yl is substituted by -NR2R3, then both the 4-position and 6-position of the pyrimidin-5-yl must be substituted by -NR2R3, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
In an alternative embodiment, the invention provides the use of a compound of formula (I) as defined above, but subject to the following alternative provisos: that: (i') when D is pyrimidin-5-yl, the 4-position of the pyrimidin-5-yl is substituted by R1, the 6-position of the pyrimidin-5-yl is substituted by -NR2R3, and L is
-C(RaRb)C(O)N(R9)-, -N(R8)C(O)C(RaRb)-, -N(R8)C(O)N(R9)-, -N(R8)C(O)O-, or -OC(O)-N(R9)- and a (l-6C)alkyl group in Ra or Rb is unsubstituted then the 2-position of the pyrimidin-5-yl cannot be substituted by hydrogen, (l-6C)alkyl or (l-6C)alkoxy (ii') when D is pyrimidin-5-yl, the 4-position of the pyrimidin-5-yl is substituted by R1, the 6-position of the pyrimidin-5-yl is substituted by -NR2R3, x+y>0 then the 2-position of the pyrimidin-5-yl cannot be substituted by (3-7C)cycloalkyl;
(iii') when D is pyrimidin-5-yl and the 2-position of the pyrimidinyl-5-yl is substituted by -NR2R3, then both the 4-position and 6-position of the pyrimidin-5-yl must be substituted by -NR2R3.
In a particular embodiment, the invention provides the use of a compound of formula (I) as defined above, but with the proviso that when L is a group -C(O)N(R9)- (CRaRb)x-Z-(CRaRb)y-, then at least one of x or y is other than 0, or Z is other than a direct bond, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
In a futher particular embodiment, the invention provides the use of a compound of formula (I) as defined above, but with the proviso that when L is a group
-C(O)N(R9)-(CRaRb)χ-Z-(CRaRb)y- then p is at least 1 and at least one R1 group is other than unsubstituted (l-6C)alkyl, unsubstituted (l-6C)alkoxy or hydroxy, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man. In yet a further embodiment, the invention provides the use of a compound of formula (I) as defined above, where L is a group -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)r, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man
For the avoidance of doubt, where L is shown, the left hand side of the formula represented is attached to the ring A and the ring hand side is attached to ring B. Thus for example, when L is a group -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the moiety
Figure imgf000012_0001
is a group of sub-formula
Figure imgf000013_0001
where variables are as defined above.
In a particular embodiment, D is other than an NR2R3 substituted fully unsaturated pyrimidin-5-yl although it may be a hydrogenated form of pyrimidin-5-yl such as dihydro- pyrimidin-5-yl, and it may carry other R1 substituent groups.
In a further particular embodiment, D is unsubstituted pyrimidin-5-yl. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms, for example (l-όC)alkoxy includes methoxy, ethoxy and isopropoxy, (l-6C)alkylamino includes methylamino, isoproylamino and ethylamino, and di-[(l-6Calkyl]amino includes dimethylamino, diethylamino andN-methyl-N-isoproylamino. The generic term aryl refers to phenyl or naphthyl, particularly phenyl.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
Suitable values for the generic radicals referred to above include those set out below.
Suitable 5 or 6 membered heteroaryl rings include, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl or pyrazinyl. Particular 5 or 6 membered heteroaryl rings include imidazolyl, pyridyl, thiazolyl, thiadiazolyl, pyrimidinyl, isoxazolyl, pyrazolyl and isothiazolyl.
Suitable saturated or partially saturated 3 to 7 membered heterocyclic rings include, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3- thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3-azabicyclo[3.1.1]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro-1,4- thiazinyl, 1-oxotetrahydrothienyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, l,l~dioxotetrahydro-4H-l,4-thiazinyl, piperidinyl or piperazinyl, more preferably tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3-yl, morpholino, l,l-dioxotetrahydro-4H-l,4-thiazin-4-yl, piperidino, piperidin-4-yl or piperazin-1-yl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2- oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5- dioxoimidazolidinyl or 2,6-dioxopiperidinyl. The saturated or partially saturated 3 to 7 membered heterocyclic rings are optionally substituted by one or more (l-6C)alkyl groups and/or by one or more hydroxy. For avoidance of doubt it will be understood that this definition includes tautomers of hydroxy substituted ring systems where the hydroxy tautomerizes to an oxo group.
Suitable 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, imidazolo[2, 1 -b]thiazolyl, dihydrocyclopentathiazolyl, tetrahydrocyclopenta[c]pyrazolyl, furo[3,2-b]furanyl, pyrrolopyrrole, thienopyrazolyl, thieno[2,3-b]thiophenyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[b]furanyl, benzo[b]thiophenyl, IH- indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indenyl, naphthalenyl, 2,3-dihydro-l,4- benzodioxinyl, l,3-benzodioxol-5-yl, decalin and norbornane. Particular 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[b]furanyl, benzo[b]thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indenyl, naphthalenyl, 2,3-dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-yl.
The bicyclic group is optionally substituted by one or more groups R6 as hereinbefore defined.
Suitable 5 or 6 membered nitrogen-containing heteroaryl ring which optionally further comprises 1 or 2 further heteroatoms independently selected from oxygen, nitrogen or sulphur include: pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, furazanyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl
The group A may particularly be attached to the ethynyl group via a carbon atom in the aryl group or in the 5 or 6 membered heteroaryl ring. The group B may particularly be attached to the group L via a carbon atom.
Suitable values for any of the substituents herein, for example the 'R' groups (R1 to R11) or for various groups within a A, B or L group include: for halo fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l-6C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-
N-methylamino and diisopropylamino; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for (l-6C)alkanoyl: formyl, acetyl and propionyl; for (l-6C)alkoxycarbonyl methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl; for hydroxy(l-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for (l-6C)alkoxy(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl,
2-methoxyethyl, 2-ethoxyethyl and 3- methoxypropyl; for (3-7C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; for ( 1 -6C)alkoxy( 1 -6C)alkoxy: methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxybutoxy, methoxyhexoxy, ethoxyethoxy, ethoxypropoxy, ethoxybutoxy, propoxypropoxy and propoxybutoxy; for (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy: methoxymethoxymethoxy, methoxyethoxyethoxy, methoxypropoxymethoxy, methoxybutoxyethoxy, methoxyhexoxymethoxy, ethoxyethoxyethoxy, ethoxypropoxyethoxy, ethoxybutoxymethoxy, propoxypropoxymethoxy and propoxybutoxymethoxy; for mono(l-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl; and for di-[(l-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl and N,N-diethylcarbamoyl.
When in this specification reference is made to a (l-4C)alkyl group it is to be understood that such groups refer to alkyl groups containing up to 4 carbon atoms. A skilled person will realise that representative examples of such groups are those listed above under (l-4C)alkyl that contain up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Similarly, reference to a (l-3C)alkyl group refers to alkyl groups containing up to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. A similar convention is adopted for the other groups listed above such as (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)alkanoyl.
It is to be understood that certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
It is also to be understood that the invention relates to all tautomeric forms of the compounds of the formula I forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
Whilst pharmaceutically-acceptable salts of compounds of the invention are preferred, other non-pharmaceutically-acceptable salts of compounds of the invention may also be useful, for example in the preparation of pharmaceutically-acceptable salts of compounds of the invention.
A suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid-addition salt of a compound of the formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Also provided as a further aspect of the invention are pro-drugs of compounds of the invention as herein before or herein after defined. Compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I). Examples of pro-drugs include in-vivo hydroly sable esters of a compound of the Formula (I).
Various forms of pro-drugs are known in the art. For examples of such pro-drug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, S, 1-38 (1992); d) H. Bundgaard, et aL, Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).
An in- vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable phaπnaceutically-acceptable esters for carboxy include Ci.6alkoxymeth.yl esters for example methoxymethyl, Ci-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters,
C3-8cycloalkoxycarbonyloxyCi.6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-6alkoxycarbonyloxyethyl esters. An in- vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in- vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Particular compounds of formula (I) include, for example, compounds of the formula I, or salts, particularly pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of R1, R2, R3, R4, R5, R6, A, B, L, m and n has any of the meanings defined hereinbefore or in paragraphs (a) to (11111) hereinafter: - (a) L is attached meta on ring A with respect to the point of attachment of the ethynyl group;
(a') L is attached para on ring A with respect to the point of attachment of the ethynyl group; (b) L is -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb, R8 and R9 are independently selected from hydrogen and (l-βC)alkyl (particularly Ra, Rb, R8 and R9 are all hydrogen );
(b') L is -N(R8)C(O)N(R9)-(CRaRb)x- wherein x is as defined above, (particularly x is 1 or 2) and Ra, Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl
(particularly Ra, Rb, R8 and R9 are all hydrogen);
(b") L is -N(R8)C(O)N(R9)-CRaRb- wherein Ra, Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb, R8 and R9 are all hydrogen );
(b" ') L is -N(R8)C(O)N(R9)-CH2- wherein R8 and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly R8 and R9 are both hydrogen );
(b" ") L is -N(R8)C(O)N(R9)-(CRaRb)χ-O-(CRaRb)y- wherein x and y are as defined above, and Ra, Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl
(particularly Ra, Rb, R8 and R9 are all hydrogen );
(b'"") L is -N(R8)C(O)N(R9HCRaRb)χ-N(R8)-(CRaRb)y- wherein R\ Rb, R8 and R9 are independently selected from hydrogen and (l-βC)alkyl (particularly Ra, Rb, R8 and R9 are all hydrogen );
(b"" ") L is -N(R8)C(O)N(R9)-(CRaRb)x-O- wherein x is as defined above, and R\ Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb, R8 and R9 are all hydrogen ); (b " " " ') L is -N(R8)C(O)N(R9)-(CRaRb)x-N(H)- - wherein x is as defined above, and Ra,
Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra,
Rb, R8 and R9 are all hydrogen );
(c) L is -N(R8)C(O)-(CRaRb)χ-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb R8 and R9 are all hydrogen );
(c') L is -N(R8)C(O)-(CRaRb)x- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen);
(c") L is -N(R8)C(O)-CRaRb- wherein Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(c" ') L is -N(R8)C(O)-CH2- wherein R8 is selected from hydrogen and (l-6C)alkyl
(particularly R8 is hydrogen ); (d) L is ~C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(d') L is -C(O)N(R9)-(CRaRb)x- wherein x is as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen);
(d") L is -C(O)N(R9)-CRaRb- wherein Ra, Rb and R9 are independently selected from hydrogen and (l-όC)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(d") L is -C(O)N(R9)-CH2- wherein R9 is selected from hydrogen and (1 -6C)alkyl (particularly R9 is hydrogen );
(e) L is ~N(R8)C(O)-O-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and Rs are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(e') L is -N(R8)C(O)-O-(CRaRb)x- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen);
(e") L is -N(R8)C(O)-O-CRaRb- wherein Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(e' ") L is -N(R8)C(O)-O-CH2- wherein R8 is selected from hydrogen and (1 -6C)alkyl (particularly R8 is hydrogen );
(f) L is -O-C(O)-N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(f ) L is -O-C(O)N(R9)-(CRaRb)x- wherein x is as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (1 -6C)alkyl (particularly Ra, Rb and R9 are all hydrogen);
(f ') L is -O-C(O)N(R9)-CRaRb- wherein Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(f ') L is -O-C(O)N(R9)-CH2- wherein R9 is selected from hydrogen and (l-6C)alkyl (particularly R9 is hydrogen ); (g) L is -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and
Z is -O- or -N(H)-, and Ra, Rb and R8 are independently selected from hydrogen and
(l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(g') L is -N(R8)S(O)2-(CRaRb)χ- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen);
(g' ') L is -N(R8)S(O)2-CRaRb- wherein Ra, Rb and R8 are independently selected from hydrogen and (l-όC)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(g" ') L is -N(R8)S(O)2-CH2- wherein R8 is selected from hydrogen and (l-6C)alkyl (particularly R8 is hydrogen );
(h) L is -S(O)2N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and
Z is -O- or -N(H)-, and Ra, Rb and R9 are independently selected from hydrogen and
(l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(h') L is -S(O)2N(R9)-(CRaRb)x- wherein x is as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen);
(h") L is -S(O)2N(R9)-CRaRb- wherein Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(h' ') L is -S(O)2N(R9)-CH2- wherein R9 is selected from hydrogen and (l-6C)alkyl (particularly R9 is hydrogen );
(i) L is -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, wherein x is as defined above, and
Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra,
Rb and R8 are all hydrogen); Particularly L is -N(H)C(O)N(H)-;
(j) Ra and Rb represent hydrogen; (j') Ra and Rb independently represent hydrogen or (l-6C)alkyl, wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring;
(j ") Ra and Rb independently represent hydrogen or (1 -6C)alkyl, wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by hydroxy or a saturated or partially saturated 5 to 6 membererd heterocyclic ring;
(j'") Ra and Rb independently represent hydrogen, methyl or ethyl, wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by hydroxy or pyrrolin-1-yl;
(k) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl;
(k') A is selected from phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl;
(k") A is phenyl or pyridyl;
(k' ") A is phenyl or pyridyl, wherein the nitrogen in the pyridyl ring is in the 3-position relateive to the alkyne bond;. (k " " ) A is phenyl or thizolyl ;
(k'"") A is phenyl, pyridyl, thiazolyl, or thiadiazolyl;'
(1) A is phenyl;
(m) A is pyridyl;
(n) A is phenyl or pyridyl and n is 0; (n1) A is phenyl or thizolyl and n is 0;
(n") A is thiazolyl;
(n'") A is thiadiazolyl;
(n" ") A is thiazolyl and n is 0 or n is 1 and R5 is (1 -4C)alkyl;
(o) A is phenyl and n is 0 or n is 1 and R5 is (l-4C)alkyl; (p) A is pyridyl and n is 0 or n is 1 and R5 is (l-4C)alkyl;
(q) A is selected from phenyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl and pyrimidyl. (r) When B is a (3-7C)cycloalkyl ring then B is selected grom cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (s) When B is a saturated or partially saturated 3 to 7 membered heterocyclic ring then B is selected from oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, , morpholinyl, 1,3- dioxolanyl, tetrahydrofuranyl, piperidyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, homopiperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, tetrahydropyridinyl, 1,2,4-oxadiazolyl and dihydrothiopyranyl; (t) When B is a 5 or 6 membered heteroaryl ring then B is selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
(u) When B is an 8, 9 or 10 membered bicyclic group which optionally contains 1,2,3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic then B is selected from 2,3-dihydro-lH-indenyl, benzodioxinyl, 1 ,2,3 ,4-tetrahydronaρhthalenyl, 1 ,2,3 ,4-tetrahydropentalene, benzofuranyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzthienyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, indolyl, and naphthyridinyl. or B is a group of the formula:
Figure imgf000023_0001
wherein W is a 5-7 membered ring (including the bridging atoms), said W ring comprising carbon atoms or optionally further heteroatoms independently selected from oxygen, nitrogen and sulphur, wherein said bicyclic ring contains no more that 4 heteroatoms in total. Examples of such rings include: pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5- c]pyrimidinyl, pyrazolo[l,5-a][l,3,5]triazinyl, 4,5-dihydropyrazolo[l,5-a]pyridmyl, 4H-pyrazolo[5, 1 -c] [1 ,4]thiazinyl, 4H-pyrazolo[5, 1 -c] [1 ,4]oxazinyl, 1 ,2-benzisoxazolyl, isoxazolo [5 ,4-b]pyridinyl, isoxazolo [5 ,4-d]pyrimidinyl, 4H-thiopyrano [3 ,4-d] isoxazolyl, 4H-pyrano[3,4-d]isoxazolyl, 7aH-indolyl, 7aH-pyrrolo[2,3-b]pyridinyl, 7aH-pyrrolo[2,3-b]pyrimidinyl, 4,7a-dihydrothiopyrano[4,3-b]pyrrolyl and 4,7a-dihydropyrano[4,3-b]pyrrolyl. (v) B is aryl, particularly phenyl; (w) B is a saturated or partially saturated 3 to 7 (particularly 4 to 6) membered heterocyclic ring that contains one or two heteroatoms (particularly one heteroatom) selected from oxygen and nitrogen; (x) B is a a 5 or 6 membered heteroaryl ring;
(y) B is a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2 or 3 (particularly 1 or 2) heteroatoms independently selected from N and O and which is saturated, partially saturated or aromatic; (z) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic;
(aa) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl;
(bb) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
(cc) B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, pyrrolidinyl, piperidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3~dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-yl; (dd) B is selected from phenyl, tetrahydopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl; (dd') B is selected from phenyl, cyclobutyl, tetrahydopyranyl, tetrahydrofuranyl,
1,4-dioxanyl, morpholinyl, furyl, pyrrolidinyl, piperidinyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; (dd") B is selected from cyclohexyl, phenyl, tetrahydopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl; (dd' ") B is selected from phenyl, imidazolyl, thienyl, and isoxazolyl;
(dd"") B is isoxazolyl; (ee) B is selected from phenyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl.
(ee') B is selected from phenyl, cyclohexyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl.
(ff) B is selected from piperidinyl, phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl;
(gg) B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
(hh) Bis selected from isoxazolyl, thiadiazolyl and pyrazolyl; (ii) Bis selected from isoxazolyl and pyrazolyl;
Gj) B is phenyl;
(kk) B is isoxazolyl;
(11) B is pyrazolyl;
(H') D is selected from pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl.
(H") D is selected from oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.
(U'") D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
(H"") D is selected from thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.
(H'"") The ring D has a nitrogen atom at the meta position with respect to the alkynyl group in Formula I.
(mm) R and R are independently selected from hydrogen, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-βC)alkyl, (l-6C)alkoxycarbonyl, (3- 6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy,
( 1 -6C)alkoxy(l -6C)alkoxy, ( 1 -6C)alkoxy( 1 -6C)alkoxy(l -6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or-N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (1- 6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl] amino, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more (for example 1 or 2) hydroxy groups; wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, wherein the (l-6C)alkyl or (l-6C)alkoxy are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R2 and/or R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l- 4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZR4 wherein z is 0, 1, 2 or 3 and R4 is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R2 and/or R3 is a (lC)alkanoyl group, then the (1 Qalkanoyl is not substituted by fluoro or hydroxy; (nn) R2 and R3 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R2 and/or R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); (oo) R2 and R3 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R2 and/or R3 are optionally independently substituted by one or more groups (for example 1 or T), which may be the same or different, as hereinbefore defined in (mm);
(pp) R2 is hydrogen and R3 is selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1- 6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (l-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); (qq) R2 hydrogen and R3 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); (rr) R2 is hydrogen and R3 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a
5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm);
(ss) R2 and R3 are independently selected from hydrogen, (l-όC)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or
6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or-N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (1- 6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl] amino, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkly]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more (for example 1 or 2) hydroxy groups; wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, wherein the (l-6C)alkyl or (1- 6C)alkoxy are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, amino, mono(l-6C)alkylamino or di- [(l-6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R2 and/or R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l- 4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZR4 wherein z is 0, 1, 2 or 3 and R4 is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl] amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R2 and/or R3 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fiuoro or hydroxy;
(tt) R2 and R3 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 and/or R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(uu) R and R are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, or a 5 or 6 membered heteroaryl ring; wherein the (l-βC)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 and/or R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(vv) R2 is hydrogen and R3 is selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1- 6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(ww) R2 is hydrogen and R3 is selected from hydrogen, (1 -6C)alkanoyl, (1 -6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(xx) R2 is hydrogen and R3 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(yy) R2 is hydrogen and R3 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(zz) R2 is hydrogen and R3 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkoxy, amino, mono(l-3C)alkylamino, di(l-3C)alkylamino, carbamoyl or-N(Rd)C(O)(l-3C)alkyl in which Rd is hydrogen or (l-3C)alkyl, or a saturated 5 or 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-4C)alkoxy and (l-4C)alkoxy(l-4C)alkoxy and the (1- 3C)alkyl groups of the mono(l-3C)alkylamino, di-[(l-3C)alkyl]amino and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more (for example 1 or 2) hydroxy groups; and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or T), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkyl, hydroxy, amino, mono(l-3C)alkylamino or di-[(l-3C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZR4 wherein z is 0, 1, 2 or 3 and R4 is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R2 and/or R3 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy; (aaa) R2 is hydrogen and R3 is selected from hydrogen, (l-3C)alkanoyl and (l-3C)alkyl; wherein the (l-3C)alkyl and the (l-3C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz);
(bbb) R2 is hydrogen and R3 is selected from hydrogen and (l-βC)alkyl (particularly (l-3C)alkyl); wherein the (l-βC)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); (ccc) R2 is hydrogen and R3 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R3 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); (ccc') R2 and R3 are both hydrogen or R2 is hydrogen and R3 is (1 -6C)alkyl wherein (l-6Calkyl) is optionally substituted by amino, mono(l-6C)alkylamino or di(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring; (ccc")R2 and R3 are both hydrogen or R2 is hydrogen and R3 is (l-6C)alkyl or (l-6C)alkanoyl, wherein (l-6Calkyl) is optionally substituted by (l-6C)alkoxy(l-6C)alkoxy;
(ccc' " ") R2 is hydrogen and R3 is selected from hydrogen, acetyl or methoxyethyoxymethyl;
(ddd) R2 and R3 are both hydrogen or R1 is hydrogen or (l-6C)alkyl and R2 is (l-6C)alkyl or (l-6C)alkanoyl; wherein (l-6Calkyl) or (l-6C)alkanoyl is optionally substituted by hydroxy, amino, mono(l-6C)alkylamino or di(l-6C)alkylamino, carbamoyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, -N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or
(l-6C)alkyl, aryl (particularly phenyl), a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring; wherein the (l-βC)alkoxy, mono(l-6C)alkylamino and -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by hydroxy; wherein an aryl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring is optionally substituted by (l-4C)alkyl, (l-4C)alkoxy or -C(O)CH2R4 wherein R4 is selected from hydroxy or di(l-6C)alkylamino.
(eee) R2 and R3 are independently selected from hydrogen, methyl, ethyl, propyl, acetyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino) ethyl, 3-(isopropylamino)propyl, 2-
(dimethylamino)ethyl, 3-(dimethylamino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3- carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholin-4-ylethyl, 3-morpholin-4- ylpropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylproρyl, 3-(4-methylpiperazin-l- yl)propyl, 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-(lH-imidazol-4-yl)ethyl, 2- pyridin-2-ylethyl, 3-(lH-imidazol-l-yl)propyl, 2-pyridin-4-ylethyl, 2,4-dimethoxybenzyl and 5 -tert-butyh'soxazol-3 -yl;
(fff) R2 is hydrogen and R3 is selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3- carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholin-4-ylethyl, 3-morpholin-4- ylpropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylρropyl, 3-(4-methylpiperazin-l- yl)propyl, 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-(lH-imidazol-4-yl)ethyl, 2- pyridin-2-ylethyl, 3-(lH-imidazol-l-yl)propyl, 2-pyridin-4-ylethyl, 2,4-dimethoxybenzyl and 5-tert-butylisoxazol-3-yl; (ggg) R2 is hydrogen and R3 is selected from hydrogen, methyl, ethyl, propyl, 3-(isopropylamino)ρropyl, 2-pyrrolidin-l-ylethyl, 5-tert-butylisoxazol-3 -yl, 3 -piperidin- 1 -ylpropyl, 2-morpholino-4-yl-ethyl, 2-pyrrolidin- 1 -ylethyl, 3-(dimethylamino)propyl, 2-hydroxyethyl and 2-piperidin-l-ylethyl;
(ggg') R1 is hydrogen and R2 is selected from R2 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is substituted by a saturated 5 or 6 membered heterocyclic ring;
(ggg") R1 is hydrogen and R2 is selected from 2-morpholino-4-yl-ethyl or 3-morpholinyl- 4-ylpropyl;
(lihh) R2 is hydrogen or methyl and R3 is selected from hydrogen, methyl, 2- hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-(2-hydroxyethoxy)ethyl, 2- methoxyethoxymethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-
(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2-(dimethylamino)ethyl, 3-
(dimethylamino)propyl, 4-(dimethylamino)butyl, 2-(dimethylamino)- 1 -methylethyl, carbamoylmethyl, 2-carbamoylethyl, 2-(2-methoxyethoxy)acetyl, 2-(2-hydroxyacetamido)ethyl, 3-[N-(2-hydroxyethyl)amino]propyl, 2-morpholin-4-ylethyl,
3-morpholin-4-ylpropyl, 2-[(l-methyl-2-moφholin-4-ylethyl), 2-pyrrolidin-l-ylethyl,
3 -pyrrolidin-1 -ylpropyl, 1 -glycoloylpyrrolidin-2-yl)methyl,
1 -(N,N-dimethylglycyl)pyrrolidin-2-yl, 2-piperazin- 1 -ylethyl, 3 -piperazin- 1 -ylpropyl,
3-(4-methylpiperazin-l-yl)propyl, 3-piperidin-l-ylpropyl, 2-(lH-imidazol-4-yl)ethyl, 2-pyridin-2-ylethyl, 3-(lH-imidazol-l-yl)propyl, 5-t-butyl-isoxazol-3-yl, 2-pyridin-4- ylethyl and and 2,4-dimethoxybenzyl;
(iii) R2 is hydrogen and R3 is selected from 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyL 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-pyrrolidin-l- ylethyl, 4-methyl-piperazin-l -ylpropyl and 3 -pyrrolidin-1 -ylpropyl; (jjj) R2 is hydrogen and R3 is selected from 2-morpholin-4-ylethyl, 3-morρholin-4-ylpropyl, 3-piperidin-l-ylpropyl, 2-ρiperidin-l-ylethyl, 2-pyrrolidin-l- ylethyl, 3-pyrrolidin-l-ylpropyl and 4-methyl-piperazin-l-yl;
(kick) R2 and R3 are both (l-6C)alkyl (particularly (l-3C)alkyl); (111) R2 is hydrogen and R3 is methyl;
(Hl') R2 and R3 are both hydrogen;
(mmm) R1 is selected from hydrogen, (l-3C)alkyl or (l-3C)alkoxy, wherein the (l-3C)alkyl and the (l-3C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l- 6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or R1 represents a group -NR2R3 as defined above; (nnn) R1 is selected from hydrogen or (l-6C)alkyl, wherein the (l-6C)alkyl group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l- 6C)alkyl] amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or R1 represents a group -NR2R3 as defined above; (ooo) R1 is selected from hydrogen and a group -NR2R3 as defined above (particularly -NH2);
(ppp) R1 is hydrogen;
(qqq) p is 0 or p is 1, 2 or 3 and R3 is independently selected from hydroxy and (l-6C)alkoxy or a group -NR2R3 as defined above (particularly -NH2); Orøl') p is 0 or p is 1 and R3 is independently selected from hydroxy and (l-6C)alkoxy or a group -NR2R3 as defined above (particularly -NH2);
(qqq') R1 is selected from hydrogen or a group -NR2R3 as defined above (particularly -NH2);
(qqq' ') R1 is selected from hydrogen or -NH2. (rrr) R1 is independently selected from (l-6C)alkyl (particularly (l-3C)alkyl);
(sss) R5 is selected from (l-6C)alkyl and (l-6C)alkoxy;
(ttt) R5 is selected from ( 1 -4C)alkyl and ( 1 -4C)alkoxy ;
(uuu) R5 is selected from methyl and methoxy;
(vw) n is 0, 1 or 2 (particularly 0 or 1, more particularly 0); (www) n is 1 or 2 and R5 is independently selected from halo, (l-6C)alkoxy and (1- 6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fiuoro;
(xxx) n is 1 or 2 and R5 is independently selected from cyano, halo, (l-6C)alkoxy and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fiuoro;
(yyy) n is 0 or I and when n is 1, R5 is (l-4C)alkyl (particularly methyl);
(zzz) n is 1 or 2 and R5 is independently selected from cyclopropyl and (l-6C)alkyl, wherein the (l-6C)alkyl groups are optionally substituted by cyano or one or more fiuoro;
(aaaa) n is 1 and R5 is (l-6C)alkyl, particularly (l-3C)alkyl; (bbbb) n is 0
(cccc) n is 1;
(dddd) R6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(Rc)C(O)(l-6C)alkyl in which R° is hydrogen or (l-6C)alkyl; or R6 is selected from (l-βC)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l- 6C)alkyl]amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring;
(eeee) R6 is independently selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or an -N(Rc)C(O)(l-6C)alkyl in which R° is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1-or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro);
(ffff) R6 is independently selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-3C)alkyl; or R6 is selected from (l-4C)alkyl or (l-4C)alkoxy, wherein the (l-4C)alkyl and the (l-4C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro); (ggg) R6 is selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
(hhhh) R6 is selected from fluoro, chloro, acetylamino, methyl, propyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy and morpholin-4-yl; [exemplification in this case] (iiii) R6 is independently selected from (l-6C)alkyl, (l-6C)alkoxy or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl or piperidin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by hydroxy (l-2C)alkyl; (iiii') R6 is independently selected from hydroxy, halo (particularly chloro or fluoro), (l-6C)alkyl, (l-6C)alkoxy, di-(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl, piperidin-1-yl or piperazin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by (1- 2C)alkyl or hydroxy(l-2C)alkyl;
(liii' ') R6 is independently selected from (l-6C)alkyl (optionally substituted 1 to 3 groups independently selected from halo, particularly fluoro), halo or (l-6C)alkoxy; (iiii'") R6 is independently selected from (l-6C)alkyl;
Gjjj) R6 is independently selected from methyl, trifluoromethyl, morpholin-4-yl or piperidin- 1 -yl, 4-hydroxymethylpiperidin- 1 -yl;
(jjjj') R6 is independently selected from methyl, methoxy, di-methylamino, hydroxy, oxo, chloro, fluoro, trifluoromethyl, morpholin-4-yl or piperidin- 1-yl, 4-hydroxymethylpiperidin- 1-yl, 4-methylpiperzin-l-yl;
Gjjj") R6 is independently selected from chloro, fluoro, trifluoromethyl, methyl or methoxy;
(jjjj " ') R6 is independently selected from t-butyl;
(kkkk) R6 is independently selected from halo, trifluoromethyl, methyl, tert-butyl, methoxy, acetylamino or morpholino.
(UU) R6 is independently selected from halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(Rc)C(O)(l-6C)alkyl wherein Rc is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or (1 -6C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro). (IUl') R6 is independently selected from hydroxy, halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(Rc)C(O)(l-6C)alkyl wherein Rc is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by a saturated 3 to 7 membered heterocyclic ring or up to three groups independently selected from halo, particularly fluoro), (l-6C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or di-(l-6C)alkylamino;. (mmmm) R6 is independently selected from halo, trifluoromethyl, cyano, methyl, isopropyl, tert-butyl, methoxy, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1- yl, 4-(hydroxymethyl)piperidin- 1 -yl and 4-methyl-piperazin- 1 -yl.
(mmmm') R6 is independently selected from hydroxy, halo, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, 1-cyanoethyl, methoxy, isopropoxy, di-methylamino, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1-yl, 4-(hydroxymethyl)piperidin-l-yl, 4-methyl-piperazin-l-yl and 4-methylpiperazin-l- ylmethyl
(mmmm' ') R6 is independently selected from halo (such as chloro), trifluoromethyl, methoxy, dimethylamino, morpholin-4-yl or piperidin-1-yl;
(mmmm"') at least one R6 group is selected from amino, mono(Ci-6alkyl)amino, di-(Ci-6- alkyl)amino such as dimethylamino; (nnnn) m is 1 or 2; (oooo) m is 1;
(pppp) m is 2;
(qqqq) Ring B-R6, where m is 1 or 2, is selected from: 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin- 1 -yl, 2-morpholin-4-ylphenyl, 2-(piperidin-l-yl)phenyl, 2-[4-(hydroxymethyl)piperidin-l-yl)]phenyl, 5-methyl-furan-2-yl and 4-morpholin-4-ylpyrimidin-5 -yl;
(qqqq') Ring B-R6, where m is 1 or 2, is selected from: 2-hydroxycyclohexyl, 2-methylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2- (dimethylamine)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin- 1-yl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, morpholin-4-yl-5- fluorophenyl, 2-(piperidin-l-yl)phenyl, 2-[4-(hydroxymethyl)piperidin-l-yl)]phenyl, 5-methyl-furan-2-yl, 2-(4-methylpiperzin-l-yl)phenyl and 4-morpholin-4-ylpyrimidin-5-yl; (qqqq'") Ring B-R6, where m is 1 or 2, is selected from 2-chloro-phenyl, 2,3- dichorophenyl, 2-fluorophenyl, 3,6-di-fluorophenyl, 2-(trifluoromethyl)phenyl, 3- (trifluoromethyl)phenyl, 2-chloro-thien-5-yl, l-methylimidazol-4-yl, 3-methoxyphenyl and 3 ,5-dimethyl-isoxazol-4-yl; (qqqq' ' ' ') Ring B-R6, where m is 1 or 2, is selected from 2-chloro-phenyl, 2,3- dichorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,6-di-fluorophenyl, 2- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-chloro-thien-5-yl, 1-methylimidazol- 4-yl, 3-methoxyphenyl and 3,5-dimethyl-isoxazol-4-yl; (qqqq'"") Ring B-R6, where m is 1 is 5-t-butyl-isoxazol-3-yl; (rrrr) Ring B-R6, where m is 1 or 2, is selected from
2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluoro-phenyl, 3,6-di-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3-cyano-phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifiuoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3 -acetylaminophenyl, 2-morpholin-4-ylphenyl, 3 -fluoro-5 -(4-methylpiperazin- 1 -yl)phenyl, 2-morpholin-4-ylphenyl, 2-(piperidin- 1 -yl)phenyl, 2-(4-hydroxymethylpiperidin- 1 -yl)phenyl, 2-oxopyrrolidin-l-yl, 2-oxo-piperidin-3-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 2,2-dimethyltetrahydropyran-4-yl, 5-methyl-furan-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5-t-butyl-l,3,4-thiadiazol-2-yl, 5-triflluoromethyl-l,3,4-thiadiazol-2-yl, 5-cyclopropyl-l,3,4-thiadiazol-2-yl, 5-ethyl-l,3,4-thiadiazol-2-yl, 5-isopropyl- 1 ,3,4-thiadiazol-2-yl, 5-ethylthio- 1 ,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methyl-isoxazol-3-yl, 5-methylisoxazol-3-yl, 5-t-butyl-isoxazol-3-yl,
3,5-dimethylisoxazol-4-yl, 4-t-butyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl, 1 -methyl- 1 H-imidazol-4-yl, 2-chloro-thien-5-yl, l-methyl-3-t-butyl-pyrazol-5-yl, l-methyl-3-cyclopropyl-pyrazol-5-yl, 1 -methyl-3 -isopropyl-pyrazol-5-yl, 1 -t-butyl-pyrazol-4-yl, l-t-butyl-3-cyclopropyl-pyrazol-5-yl, l-ethyl-pyrazol-3-yl, l-isopropyl-pyrazol-3-yl, 5- isopropyl-l,3,4-oxadiazol-2-yl, 4-trifluoro-pyrid-2-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl; 5-methylpyrazin-2-yl and 4-moφholin-4-ylpyrimidin-5-yl;
(rrrr') Ring B-R6, where m is 1 or 2, is selected from
2-hydroxycyclohexyl, phenyl, 2-methylphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro- phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluoro-phenyl, 3,6-di-fluorophenyl, 2- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- isopropoxyphenyl, 3-cyano-phenyl, 3-(l-cyanoethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5 -(trifluoromethyl)phenyl, 2-(dimethylamine)phenyl, 3 -acetylaminophenyl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 2-morpholin-4-yl-5-fluorophenyl, 2-(4- methylpiperazin- 1 -yl)phenyl, 3 -fluoro-5-(4-methylpiρerazin- 1 -yl)plienyl, 2-(piperidin- 1 -yl)phenyl, 2-(4-hydroxymethylpiperidin- 1 -yl)phenyl, 2-oxopyrrolidin-l-yl, 2-oxo-piperidin~3-yl, l-methylρiperidin-4-yl, l-propylpiperidin-4-yl, 4-methyl-piperazin- 1 -ylmethylphenyl, 2,2-dimethyltetrahydropyran-4-yl, 5-methyl-furan-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5-t-butyl-l,3,4-thiadiazol-2-yl, 5-triflluoromethyl~l,3,4-thiadiazol-2-yl, 5-cyclopropyl-l,3,4-thiadiazol-2-yl, 5-ethyl-l,3,4-thiadiazol-2-yl, 5-isoρropyl-l,3,4-thiadiazol-2-yl, 5-ethylthio- 1 ,3 ,4-thiadiazol-2-yl, 3 -methylisoxazol-5-yl, 4-methyl-isoxazol-3 -yl, 5-methylisoxazol-3-yl, 5~t-butyl-isoxazol-3-yl, 3,5-dimethylisoxazol-4-yl, 4-t-butyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl,
1 -methyl- lH-imidazol-4-yl, 2-chloro-thien-5-yl, l-methyl-3-t-butyl-pyrazol-5-yl, 1 -methyl-3 -cy clopropyl-pyrazol-5 -yl, 1 -methyl-3 -isopropyl-pyrazol-5 -yl, l-t-butyl-pyrazol-4-yl, l-t-butyl-S-cyclopropyl-pyrazol-S-yl, l-ethyl-pyrazol-3-yl, 1 -isopropyl-pyrazol-3 -yl, 5-isopropyl- 1 ,3 ,4-oxadiazol-2-yl, 4-trifluoro-pyrid-2-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;
5-methylpyrazin-2-yl and 4-morpholin-4-ylpyrimidin-5-yl; benzodioxolyl;
(rrrr") Ring B-R6, where m is 1 or 2, is selected from
2-hydroxycyclohexyl, phenyl, 2-methylphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro- phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluoro-phenyl, 3,6-di-fluorophenyl, 2- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- isopropoxyphenyl, 3-cyano-phenyl, 3-(l-cyanoethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-(dimethylamine)phenyl, 3 -acetylaminophenyl, 2-moφholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 2-morpholin-4-yl-5-fluorophenyl, 2-(4- methylpiperazin-l-yl)phenyl, 3-fluoro-5-(4-methylpiperazin-l-yl)phenyl, 2-(piperidin- 1 -yl)phenyl, 2-(4-hydroxymethylρiperidin- 1 -yl)phenyl, 2-oxopyrrolidin-l-yl, 2-oxo-piperidin-3-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 4-methyl-piperazin- 1 -ylmethylphenyl, 2,2-dimethyltetrahydropyran-4-yl, 5-methyl-furan-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5-t-butyl-l,3,4-thiadiazol-2-yl, 5-triflluoromethyl-l,3,4-thiadiazol-2-yl, 5-cyclopropyl-l,3,4-thiadiazol-2-yl, 5-ethyl-l,3,4-thiadiazol-2-yl, 5-isopropyl-l,3,4-thiadiazol-2-yl, 5-ethylthio-l ,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methyl-isoxazol-3-yl, 5-methylisoxazol-3-yl, 5-t-butyl-isoxazol-3-yl, 3,5-dimethylisoxazol-4-yl, 4-t-butyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl,
1 -methyl- lH-imidazol-4-yl, 2-chloro-thien-5-yl, l-methyl-3-t-butyl-pyrazol-5-yl, l-methyl-3-cyclopropyl-pyrazol-5-yl, l-methyl-3-isopropyl-pyrazol-5-yl, l-t-butyl-pyrazol-4-yl, l-t-butyl-3-cyclopropyl-pyrazol-5-yl, l-ethyl-pyrazol-3-yl, l-isopropyl-pyrazol-3-yl, 5-isopropyl-l,3,4-oxadiazol-2-yl, 4-trifluoro-pyrid-2-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;
5-methylpyrazin-2-yl, 4-morpholin-4-ylpyrimidin-5-yl; benzodioxolyl, and 2- (dimethylamino)phenyl;
(ssss) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and Lis attached meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)r or -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)ys
Z is a direct bond, -O- or -N(R8)- x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4,
R8, R9, Ra and Rb represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
(particularly a (l-6C)alkyl group in Ra and Rb is unsubstituted);
(tttt) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and
Lis attached meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or
-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-;
Z is a direct bond, -O- or -N(R8)- x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4,
R8, R9, Ra and Rb represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
(particularly a (l-6C)alkyl group in Ra and Rb is unsubstituted);
D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; (uuuu) A is phenyl; n is 0; and B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic;
(ww) A is phenyl; n is 0; and
B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl; (wwww)A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
Lis attached meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or
-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)r;
Z is a direct bond, -O- or -N(R8)- x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4,
R8, R9, Ra and Rb represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
(particularly a (l-6C)alkyl group in Ra and Rb is unsubstituted); B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
(xxxx) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
Lis attached meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or
-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)r;
Z is a direct bond, -O- or -N(R8)- x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4,
R8, R9, Ra and Rb represents hydrogen or (l-6C)alkyl, and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
(particularly a (l-6C)alkyl group in Ra and Rb is unsubstituted); and B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
(yyyy) m is 0, I or 2 (particularly 1 or 2); (zzzz) B is selected from cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
1,3,5-triazinyl, 2,3-dihydro-l,4-benzodioxinyl and l,3-benzodioxol-5-yl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
(aaaaa) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
R6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-βC)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro);
(bbbbb) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
(ccccc) B is phenyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
(ddddd) B is phenyl; m is 1 or 2; and
R6 is independently selected from fluoro and trifluoromethyl;
(eeeee) B is isoxazolyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy; (fffff) B is isoxazolyl; m is 1 or 2; and
R6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (ggggg) B is pyrazolyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy; (hhhhh) B is pyrazolyl; m is 1 or 2; and
R6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (iiiii) B is thiadiazolyl; m is 1 or 2; and R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy and butoxy; (jjjjj) B is thiadiazolyl; m is 1 or 2; and R6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (cccc) Ring B-R6 wherein m is 0, 1 or 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 2-fluorophenyl, 3 -fluorophenyl, A- fluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5- (trifluoromethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 5-tert-butyl- 1 ,3 ,4-thiadizol-2-yl, 5-methyl- 1 ,3 ,4-thiadizol~2-yl, 5-cyclopropyl- 1 ,3 ,4-thiadizol-2-yl, 1 -methyl-3-cyclopropyl- pyrazol-5-yl, l-tert-butyl-3-cyclopropyl-pyrazol-5-yl, 3-methylisothiazol-5-yl, 3- methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 4-
(trifluoromethyl)pyridin-2-yl, 2-oxopiperidin-3-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 2,3-dihydro-l,4-benzodioxinyl, l,3-benzodioxol-5-yl, 2-morpholin-4-ylphenyl, 3- morpholin-4-ylphenyl, 4-morpholin-4-ylphenyl, l-methylpiperidin-4-yl, 1-ethylpiperidin- 4-yl and l-propylpiperidin-4-yl; and (kkkkk) Ring B-R6 wherein m is 1 or 2 is selected from 2-fluorophenyl, 3-fluorophenyl, 4-fiuorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoroinetliyl)pl1enyl, 2-fluoro-5~(trifluorornethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 3,4-dichloroplienyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,
2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 5 -tert-butyl- 1 , 3 ,4-thiadizol-2- yl, 5-methyl-l,3,4-thiadizol-2-yl, 5-cyclopropyl- 1, 3, 4-thiadizol-2-yl, 3-cyclopropyl- pyrazol-5-yl, l-tert-butyl-S-cyclopropyl-pyrazol-S-yl, 3-methylisothiazol-5-yl, 3- methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 4- (trifluoromethyl)pyridin-2-yl, 2-oxopiperidin-3-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 4-morpholin-4-ylphenyl, 1- methylpiperidin-4-yl, l-ethylpiperidin-4-yl and l-propylpiperidin-4-yl.
(11111) R1 and R2 are both hydrogen, R3 and R4 are both hydrogen, n is 0, L is -NHC(O)NH-, and ring B-R6, where m is 1 or 2, is selected from 3-acetylaminophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl,, 3,4-dichloro-phenyl, 2-morpholin-4-ylphenyl, 5-tert-butyl- 1 ,3,4-thiadiazol-2-yl, 3-methylisothiazol-5-yl, 3-methylisoxazol-5-yl, 5-tert-butylisoxazol-3 -yl, 1 -methyl-3 -tert-butyl-pyrazol-5-yl, 1 -methylpiperidin-4-yl, 1 -propylpiperidin-4-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;
(mmmmm) Ry is a group NR1R2, Rx is a group R3a and Rz is a group R4a and R3a and R4a are hydrogen, ring A is phenyl or pyridyl, n is 0 or 1, and when n is 1, R5 is methyl, L is -NHC(O)NH-CH2-, ring B-R6 is selected from 2-chloro-phenyl, 2-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3 -methoxy -phenyl, 2-methylaminoρhenyl, 2-morpholin~4-ylphenyl, or 2-piperin- 1 -ylphenyl.
A particular embodiment of the compounds of the Formula I is a compound of the Formula Ib:
Figure imgf000048_0001
Formula Ib wherein
A is selected from phenyl or pyridyl; B is selected from isoxazolyl or pyrazolyl; D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; and R1, R2, R3, R5, R6, L, n, m and p are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof.
Certain compounds of formula (I) are novel and these form a further aspect of the invention. In particular, the invention provides a compound of formula (IC)
Figure imgf000048_0002
where A, B, D, R1, R5, R6, p, n and m as defined above in relation to formula (I), subject to the following provisos:
A) when L is a group -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or
N(R8)C(O)-(CRaRb)x-Z-(CRaRb)r, then at least one of x or y is other than 0, or Z is other than a direct bond; B) where L is a group C(RaRb)C(O)N(R8)-(CRaRb)x-Z-(CRaRb)y, x is 0, y is 0 and Z is a direct bond, then B is other than a substituted l,4,5,6-tetrahydro-cyclopentapyrazol-3-yl group
C) when L is meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-,
-N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or - -N(R8)C(O)-O-(CRaRb)x-Z-(CRaRb)y- where x and y are both 0 and Z is a direct bond, then ring A is other than a thiazolyl ring, and
D) when L is -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, where Z is a direct bond, then x + y is other than 1, E) when L is a group -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-,
-N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or -S(O)2N(R9)-(CRaRb)x-Z-(CRaRb)r, and x and y are both 0 and Z is a direct bond, then D is other than a thiazole group, and F) when L is a group -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, where x and y are both zero and Z is a direct bond, and where B is a 6-membered aryl group, a 6 membered nitrogen containing heteroaryl group, or a 9 or 10 membered bicyclic group which contains nitrogen atoms, then R6 is other than an optionally substituted N-linked pyrolidine group. In a particular embodiment of the compounds of formula (IC), when L is a group C(RaRb)C(O)N(R8)-(CRaRb)x-Z-(CRaRb)y, then at least one of x or y is other than 0, or Z is other than a direct bond. In a further particular embodiment of compounds of formula (IC), when L is a group C(RaRb)C(O)N(R8)-(CRaRb)x-Z-(CRaRb)y, x is 0, y is 0 and Z is a direct bond, then B is other than an 8 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur.
Suitably in compound of formula (IC), A is other than pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and in particular A is phenyl.
In one embodiment, in the compounds of formula (IC) x is greater than 0 and/or Z is other than a direct bond.
Particular examples of groups A, B, D, R1, R5, R6, p, n and m in formula (IC) are those described above in relation to formula (I)5 but conditional upon provisos (A) to (D). A compound of the Formula I, or a pharmaceutically acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a novel compound of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
According to a further aspect of the present invention provides a process for preparing a compound of formula IC or a pharmaceutically acceptable salt thereof (wherein R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, L , ring A, ring B, ring D, n, m and p are, unless otherwise specified, as defined in formula I) as described schematically below.
Process (a) For compounds of the formula IC wherein L is
-N(R8)C(O)N(H)-(CRaRb)χ-Z-(CRaRb)y-, the reaction of a compound of the formula II:
Figure imgf000050_0001
wherein R1 , R5, R8, n, p, D and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an isocyanate of the formula III:
Figure imgf000050_0002
wherein R , Ra, R , x, y m, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (b) For compounds of the formula IC wherein L is
-N(R8)C(O)N(H)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula II as defined above with an aryl carbamate of the formula IV:
Figure imgf000051_0001
IV wherein Ar is a suitable aryl group, for example phenyl, and Z, R6, Ra, Rb, x, y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (c) For compounds of the formula IC wherein L is -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(RaRb)N(R8)C(O)~(CRaRb)x-Z~(CRaRb)y-, the reaction of a compound of the formula V:
Figure imgf000051_0002
V
wherein W is -C(RaRb)- or a direct bond and R1, R5, R8, Ra, Rb, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a heterocycle of the formula VI:
Figure imgf000051_0003
Vl wherein Lg2 is a suitable displaceable group, for example halogeno (such as chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy , and Z, R6, Ra, Rb, m, x, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (d) For compounds of the formula IC wherein L is
-N(R8)C(O)N(H)-(CRaRb)x-Z-(CRaRb)y- the reaction of a compound of the formula II as defined above with a trichloroacetylamine of the formula VII:
Figure imgf000052_0001
VII wherein R6, Ra, Rb, x, y, m, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (e) For compounds of the formula IC wherein L is -N(H)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of an isocyanate of the formula VIII:
Figure imgf000052_0002
VIII wherein R1, R5, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula IX
Figure imgf000052_0003
IX wherein R6, R9, Ra, Rb, m, x, y, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary, or Process (f) For compounds of the formula IC wherein L is -N(H)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula X:
Figure imgf000053_0001
X wherein Ar is a suitable aryl group, for example phenyl, and R1, R5, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula IX as defined above. Process (R) For compounds of the formula IC wherein L is -C(RaRb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula XI:
Figure imgf000053_0002
Xl wherein Lg2 is a suitable displaceable group as described above, W is -C(RaRb)- or a direct bond and Z, R1, R5, Ra, Rb, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula XII:
Figure imgf000053_0003
XII wherein R6, R9, Ra, Rb, m, x, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process Qi) For compounds of the formula IC wherein L is N(R8)C(O)-O-, the reaction of a compound of the formula II as defined above with a compound of the formula XIII:
Figure imgf000054_0001
XIII wherein Lg1 is a suitable displaceable group, for example halogeno (such as fluoro, chloro or bromo) and R6, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (T) For compounds of the formula IC wherein L is -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)r, the reaction of a compound of the formula XIV:
Figure imgf000054_0002
XIV wherein R1, R5, R8, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an activated sulphonyl of the formula XV:
Figure imgf000054_0003
wherein R6, Ra, Rb, x, y m, Z and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary and wherein Lg1 is a suitable displaceable group for example halogeno (such as fluoro, chloro or bromo); or
Process ffl For compounds of the formula IC wherein L is -S(O)2N(R8)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula XVI
Figure imgf000055_0001
XVl wherein R1, R5, n, p, A, D and Lg1 have any of the meanings defined hereinbefore except that any functional group is protected if necessaiy, with an amine of the formula XVII:
Figure imgf000055_0002
XVII wherein R6, R8, Ra, Rb, x, y m, Z and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process Tk) For compounds of formula IC wherein Z is -O- or -N(Ra)-, the reaction of a compound of formula XVIII
Figure imgf000055_0003
XVIII wherein Y is -S(O)2N(R8)- or -N(R8)S(O)2- and R1, R5, R8, Ra, Rb, n, p, x, y, A, D and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of formula XIX,
Figure imgf000055_0004
XIX wherein Lg1 is a suitable displaceable group, for example halogeno (such as fluoro, chloro, bromo), O-tosyl, O-mesyl or τrifluorosulphonyloxy and R6, Ra, Rb, y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
Process (1) For compounds of formula IC wherein Z is -O- or -N(Ra)-, the reaction of a compound of formula XX
Figure imgf000056_0001
XX wherein Y is -S(O)2N(R8)- or -N(R8)S(O)2- and Lg2 is a suitable displaceable group, as described above and R1, R5, R8, Ra, Rb, n, p, x, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of formula XXI,
Figure imgf000056_0002
XXI wherein R6, Ra, Rb, m, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (m) For compounds of formula IC wherein an R1 group is -NR2R3 The reaction of a compound of the foπnula XXII:
Figure imgf000057_0001
XXII wherein Lg3 is a suitable displaceable group for example halogeno (such as fluoro, chloro, bromo or iodo), methylsulfonyl, methylsulphinyl methylthio or aryloxy (such as phenoxy) and R1, R5, R6, n, m, p, A, B, D and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR2R3, wherein R2 and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (n) The reaction of a compound of the formula XXIII:
Figure imgf000057_0002
XXIII wherein Lg4 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifmoromethylsulfonyloxy) and R5, R6, n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an heterocyle of the formula XXIV:
Figure imgf000057_0003
XXIV wherein R1, p and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (o) The reaction of an alkyne of the formula XXV:
Figure imgf000058_0001
XXV wherein R5, R6, n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessaiy, with a heterocycle of the formula XXVI:
Figure imgf000058_0002
XXVl wherein Lg5 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifluoromethylsulfonyloxy) and R1, p and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary; and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt or solvate. Reaction Conditions for Process (a)
The reaction of process (a) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an amine such as pyridine or a dipolar aprotic solvent such asJ^,N-dimethylformamide or N,N-dimethylacetamide. The reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 600C, preferably at or near ambient temperature. Reaction Conditions for Process (b)
The reaction of process (b) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine). The reaction of process (b) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 1200C, preferably from about 80°C to about 1000C.
Conveniently, this reaction may also be performed by heating the reactants in a sealed vessel using a suitable heating apparatus such as a microwave heater. Reaction Conditions for Process (c)
When Lg2 is hydroxy, the reaction of process (c) is conveniently carried out in the presence of a suitable coupling agent. A suitable coupling agent is, for example, a suitable peptide coupling agent, for example O-(7-azabenzotriazol-l-yl)~N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or a suitable carbodiimide such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole (CDI), optionally in the presence of a catalyst such as dimethylaminopyridine or hydroxybenzotriazole. When Lg2 is any suitable displaceable group as described above, the reaction of process (d) may conveniently be carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene. Another suitable base is, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, caesium carbonate or calcium carbonate.
The reaction of process (c) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from about O0C to about 120°C, preferably at or near ambient temperature.
Reaction Conditions for Process fd) The reaction of process (d) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate, such as sodium carbonate, potassium carbonate, caesium carbonate or calcium carbonate. The reaction of process (d) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 12O0C, preferably from about 1000C to about 1200C.
Conveniently, this reaction may also be performed by heating the reactants in a sealed vessel using a suitable heating apparatus such as a microwave heater.
Reaction Conditions for Process (e)
The reaction of process (e) is conveniently carried out under the conditions as described above for process (a).
Reaction Conditions for Process ffl
The reaction of process (f) is conveniently carried out under the conditions as described above for process (b).
Reaction Conditions for Process ("g") The reaction of process (g) is conveniently carried out under the conditions as described above for process (c).
Reaction Conditions for Process (h)
The reaction of process (h) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate. The reaction of process (h) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride or an ether such as tetrahydrofuran or 1,4-dioxane. The reaction is conveniently carried out at a temperature in the range, for example, from about - 100C to about 3O0C, preferably at or near 00C. Reaction Conditions for Process (i)
The reaction of process (i) is conveniently carried out in the presence of a suitable solvent or diluent, such as methylene chloride, THF or pyridine, in the presence of a base such as triethylamine or pyridine. The reaction is conveniently carried at a temperature between ambient temperature and 1000C. Reaction Conditions for Process Cf)
The reaction of process (j) is conveniently carried out under the conditions as described above for process (i). Reaction Conditions for Process (k) The reaction of process (k) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
The reaction of process (k) is conveniently carried out in the presence of a suitable solvent or diluent, for example tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide. The reaction is conveniently carried out at a temperature in the range, for example, from about ambient temperature to about 1000C, and under atmospheric pressure. Reaction Conditions for Process (1) The reaction of process (1) is conveniently carried out under the conditions as described above for process (k). Reaction Conditions for Process (rn)
The reaction of process (m) may be carried out in the presence of a catalytic amount of a suitable acid. A suitable acid is, for example, hydrogen chloride, The reaction of process (m) may conveniently be carried out in the absence or the presence of a suitable inert solvent or diluent. A suitable inert solvent or diluent, when used, is for example an alcohol such as ethanol, isopropanol or butanol or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 12O0C, preferably from about ambient temperature to about 600C. Reaction Conditions for Process Cn)
The reaction of process (n) is conveniently carried out in the presence of a suitable palladium catalyst, optionally in combination with a suitable copper catalyst. A suitable palladium catalyst is, for example, bis(triphenylphosphine)palladium dichloride, [1,1'- bis(diphenylphosphino)ferrocene] palladium dichloride or tetrakis(triphenylphosphine)palladium(0). A suitable copper catalyst is, for example, copper (I) iodide.
The reaction of process (n) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base, such as a trialkylamine (for example triethylamine) or tetramethylguanidine. The reaction of process (n) may conveniently be carried out in the absence or presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from about -200C to about 1000C. Reaction Conditions for Process Co)
The reaction of process (o) is conveniently carried out under the conditions as described above for process (n). Starting Materials for Process (a) Compounds of the formula II may be obtained by conventional procedures. For example, compounds of the formula II may be obtained by reaction of a hetercycle of the formula XXVII with an alkyne of the formula XXVIII as illustrated in Reaction Scheme 1:
Figure imgf000063_0001
XXVIII
XXVII
Figure imgf000063_0002
Reaction Scheme 1 wherein Lg4 is a suitable displaceable group as described above and R1, R5, R8, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
The reaction of Reaction Scheme 1 is conveniently carried out under the conditions as described above for process (n).
Alternatively, compounds of the formula II may be obtained by reaction of a pyrimidine of the formula XXVII with a protected alkyne of the formula XXIX and then with an amine of the formula XXX as illustrated in Reaction Scheme 2:
Figure imgf000064_0001
XXVII XXI
Figure imgf000064_0002
Reaction Scheme 2 wherein Lg4 in the compounds of the formulae XXVII and XXX are each a suitable displaceable group as described above, Pg is a suitable protecting group, for example a trialkylsilyl group, such as trimethylsilyl or tert-butyldimethylsilyl or Me2(OH)C- and R1, R5, R8, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
Step (i) of Reaction Scheme 2 is the coupling of a protected alkyne of the formula XXIX to a heterocycle of the formula XXVII. Step (i) is carried out under conditions as described above for process (n). Step (ii) of. Reaction Scheme 2 is the deprotection of the alkyne under basic or acidic conditions to provide an unsubstituted alkyne. A person skilled in the art would readily be able to select the appropriate conditions for deprotection in step (ii). Step (iii) of Reaction Scheme 2 is the coupling of the alkyne to an amine of the formula XXX. Step (iii) of Reaction Scheme 2 is carried out under conditions as described above for process (o).
Alternatively, compounds of the formula II may be obtained by reaction of a compound of the formula XXXI, wherein R1, R5, R8, n, p, A and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR2R3 wherein R1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary ,using reaction conditions as described above for process (n).
Figure imgf000065_0001
XXXI
The starting materials of the formulae XXVII, XXVIII, XXIX, XXX and XXXI and the amine HNR2R3 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Isocyanates of the formula III are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. For example, as the skilled person would appreciate, the isocyanates can conveniently be prepared from the corresponding acids or acid chlorides via a Curtis reaction with for example azide or diphenylphosphoryl azide. Alternatively, the isocyanates can conveniently be prepared by reaction of the corresponding amine with phosgene or a phosgene equivalent, for example triphosgene, diphosgene or N,N'-carbonyldiimidazole (March J., Adv. Org. Chem., 4th edition, 1992, page 1290, Wiley Interscience). Starting Materials for Process (b)
Compounds of the formula II may be obtained by conventional procedures as discussed above.
Aryl carbamates of the formula IV are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. For example, the aryl carbamates can be prepared by reaction of an amine of the formula XXXII with an arylchloroformate as illustrated in Reaction Scheme 3:
Figure imgf000065_0002
XXXII IV
Reaction Scheme 3 wherein R6, Ra, Rb, m, x, y, B, Z and Ar have any of the meanings defined hereinbefore except that any functional group is protected if necessary. The reaction of Reaction Scheme 3 is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine).
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ether such as tetrahydrofuran or 1,4-dioxane. The reaction is conveniently carried out at a temperature in the range, for example, from about -20°C to about 1000C, preferably at or near 00C.
The starting material of the formula XXXII and the arylchloroformate are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (c)
Compounds of formula V are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Compounds of the formula VI may be obtained by conventional procedures as discussed above. Starting Materials for Process (d)
Compounds of the formula II may be obtained by conventional procedures as discussed above.
Trichloroacetylamines of the formula VII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (e)
As the skilled person would appreciate, isocyanates of the formula VIII can conveniently be prepared from the corresponding acids or acid chlorides via a Curtis reaction for example with azide or diphenylphosphoryl azide. Alternatively, the isocyanates can conveniently be prepared by reaction of the corresponding amine with phosgene or a phosgene equivalent, for example triphosgene, diphosgene or N,N'- carbonyldiimidazole (March J., Adv. Org. Chem., 4th edition, 1992, page 1290, Wiley Interscience).
Amines of the formula IX are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (f)
Compounds of the formula X are commercially available or they are known in the literature, or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials. Amines of formula IX are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Starting Materials for Process (g)
Compounds of the formula XI may be obtained by conventional procedures as discussed above. Amines of the formula XII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Starting Materials for Process (h)
Compounds of the formula II may be obtained by conventional procedures as discussed above. Compounds of the formula XIII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Starting Materials for Process (T)
Compounds of the formula XIV may be obtained by conventional procedures as discussed above. Activated sulphonyls of the formula XV are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
For example, as the skilled person would appreciate, the activated sulphonyls can conveniently be prepared from the corresponding sulphonic acids by reaction with phosphorous oxy chloride or thionyl chloride by heating under reflux. Starting Materials for Process (j)
Compounds of the formula XVI may be obtained by procedures analagous to those described above for the preparation of compounds of formula II. The skilled man would appreciate that the group -NHR8 in reaction schemes 1 and 2 could be replaced by a suitable group that can be readily converted into -SO2-Lg1, for example -SO3H (converted into -SO2-Lg1 by chlorination), -SC(=NH)-NH2 (converted into -SO2-Lg1 by oxidative halogenation), bromo or iodo (converted into -SO2-Lg1 through the formation of a
Grignard followed by reaction with sulphuryl chloride) or an amino group (converted into -SO2-Lg1 through formation of a diazonium salt followed by reaction with sulphur dioxide and copper (I) chloride)
Compounds of the formula XVII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (k)
Compounds of the formula XVIII may be obtained by conventional procedures analogous to the procedures for the preparation of compounds of formula II in 'Starting Materials for Process (a)' above.
Compounds of formula XIX are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (1)
Compounds of the formula XX may be obtained by conventional procedures analogous to the procedures for the preparation of compounds of formula II in 'Starting Materials for Process (a)' above. Compounds of formula XXI are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (m)
As the skilled person would appreciate, compounds of the formula XXII can be prepared using similar processes to those described above using the appropriate starting materials, for example, wherein the starting materials carry an, optionally protected, group Lg3 in place of the -NR2R3 group.
Amines of the formula HNR2R3 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (n) Compounds of formula XXIII are commercially available or they are known in the literature, or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials. For example, compounds of the formula XXIII wherein L is -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- may conveniently be obtained by reaction of an amine of the formula XXXIII with an activated sulphonyl of the formula XXXIV (as described above) as illustrated in Reaction Scheme 4:
Figure imgf000069_0001
XXXIl!
Figure imgf000069_0002
XXIII
Reaction Scheme 4 wherein Lg4 is a suitable displaceable group as described above, L is -N(R8)S(O)2-(CRaRb)χ-Z-(CRaRb)y- and R5, R6, R8, Ra, Rb, n, m, x, y, A, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
The reaction of Reaction Scheme 4 is conveniently carried out under the conditions as described above for process (a).
The starting materials of the formulae XXXIII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Alkynes of the formula XXIV are commercially available or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials. For example, compounds of the formula XXIV may conveniently be obtained by reaction of a heterocycle of the formula XXXIV:
Figure imgf000069_0003
XXXIV wherein Lg4 is a suitable displaceable group as described above and R1, p and D have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with trimethylsilylacetylene or 2-methyl-3-butyn-2-ol conveniently under the conditions as described above for process (c), followed by the removal of the protecting group using standard procedures known in the art. Starting Materials for Process (o)
Compounds of the formula XXV can be prepared using procedures analogous to processes (a) as described above.
Compounds of the formula XXVI are commercially available or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials.
Compounds of the formula I can be converted into further compounds of the formula I using standard procedures conventional in the art.
Examples of the types of conversion reactions that may be used include introduction of a substiruent by means of an aromatic substitution reaction or of a nucleophilic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art.
Particular examples of aromatic substitution reactions include the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under
Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of nucleophilic substitution reactions include the introduction of an alkoxy group or of a monoalkylamino group, a dialkyamino group or a N-containing heterocycle using standard conditions. Particular examples of reduction reactions include the reduction of a carbonyl group to a hydroxy group with sodium borohydride or of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating.
An example of a suitable conversion reaction is the conversion of a carbamate compound of the formula I wherein R1, R2, R3, R4, R5, n and A are as defined in claim 1, L is N(H)C(O)-O-, B is an optionally substituted phenyl group, to a compound of the formula I wherein L is N(H)C(O)NH and R1, R2, R3, R4, R5, n, B and A are as defined in claim 1. Such a conversion may be achieved using standard procedures, for example by reaction of the carbamate with an appropriate amine, for example under conditions as described above for process (b).
Another example of a suitable conversion reaction is the conversion of a compound of the formula I wherein R2, R3, R4, R5, R6, n, m, A, B and L are as defined in claim 1 and R1 and/or R2 is hydrogen to a compound of the formula I wherein R1 and/or R2 is, for example, an optionally substituted (l-6C)alkoxycarbonyl group. Such a conversion may be achieved using standard procedures, for example by substitution of one or both of the hydrogen atoms R1 and/or R2 for a desired, optionally substituted, (l-6C)alkoxycarbonyl group. Certain compounds of Formula I are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula I and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Isomers may be resolved or separated by conventional techniques, e.g. chromatography or fractional crystallisation. Enantiomers may be isolated by separation of aracemic or other mixture of the compounds using conventional techniques (e.g. chiral High Performance Liquid Chromatography (HPLC)). Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) or may be made with achiral starting materials and chiral reagents. All stereoisomers are included within the scope of the invention.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
It will also be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
It is believed that certain intermediate compounds of the Formulae II, XIV, XVI, XIX, XX and VIc are novel and are herein claimed as another aspect of the present invention. Biological Assays
The following assays can be used to measure the effects of the compounds of the present invention as Tie2 inhibitors in vitro and as inhibitors of Tie2 autophosphorylation in whole cells. a. In vitro receptor tyrosine kinase inhibition assay
To test for inhibition of Tie2 receptor tyrosine kinase, compounds are evaluated in a non-cell based protein kinase assay by their ability to inhibit the protein kinase enzyme phosphorylation of a tyrosine containing polypeptide substrate in an ELISA based microtitre plate assay. In this particular case, the assay was to determine the IC50, for three different recombinant human tyrosine kinases Tie2, KDR and Fit.
To facilitate production of the tyrosine kinases, recombinant receptor genes were produced using standard molecular biology cloning and mutagenesis techniques. These recombinant proteins fragments encoded within these genes consist of only the intracellular portion C-terminal portion of the respective receptor, within which is found the kinase domain. The recombinant genes encoding the kinase domain containing fragments were cloned and expressed in standard baculovirus/Sf21 system (or alternative equivalent).
Lysates were prepared from the host insect cells following protein expression by treatment with ice-cold lysis buffer (2OmM N-2-hydroxyethylpiperizine- N'-2-ethanesulphonic acid (HEPES) pH7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl2, 1 mM ethylene glycol-bis (β-aminoethyl ether) N',N',N',N'- tetraacetic acid (EGTA), plus protease inhibitors and then cleared by centrifugation. Tie2, KDR and Fltl lysates were stored in aliquots at -80 0C.
Constitutive kinase activity of these recombinant proteins was determined by their ability to phosphorylate a synthetic peptide (made up of a random co-polymer of Glutamic Acid, Alanine and Tyrosine in the ratio of 6:3:1). Specifically, Nunc Maxisorb™ 96-well immunoplates were coated with 100 microlitres of synthetic peptide Sigma P3899 (lmg/ml stock solution in PBS diluted 1:500 in PBS prior to plate coating) and incubated at 4 0C overnight. Plates were washed in 50 mM HEPES pH 7.4 at room temperature to remove any excess unbound synthetic peptide.
Tie2, KDR or Fltl activities were assessed by incubation of the appropriate freshly diluted lysates (1:200, 1:400 and 1:1000 respectively) in peptide coated plates for 60 minutes (Tie2) or 20 minutes for (KDR, Fit) at room temperature in 100 niM HEPES pH 7.4 , adenosine trisphosphate (ATP) at 5 micromolar (or Km concentration for the respective enzyme, 10 mM MnCl2, 0.1 mM Na3VO4, 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100 together with the test comρound(s) in dissolved in DMSO (final
5 concentration of 2.5%) with final compound concentrations ranging from 0.05 micromolar -100 micromolar. Reactions were terminated by the removal of the liquid components of the assay followed by washing of the plates with PBS-T (phosphate buffered saline with 0.5% Tween 20) or an alternative equivalent wash buffer.
The immobilised phospho-peptide product of the reaction was detected by o immunological methods. Firstly, plates were incubated for 4 hours at room temperature with murine monoclonal anti-phosphotyrosin -HRP (Horseradish Peroxidase) conjugated antibodies (4G10 from Upstate Biotechnology UBI 16-105). Following extensive washing with PBS-T, HRP activity in each well of the plate was measured colorimetrically using 22'-Azino-di-[3-ethylbenzthiazoline sulfonate (6)] diammonium salt crystals ABTS 5 (Sigma P4922 - prepared as per manufactures instructions) as a substrate incubated for 30- 45 minutes to allow colour development, before lOOul of IM H2SO4 was added to stop the reaction.
Quantification of colour development and thus enzyme activity was achieved by the measurement of absorbance at 405nm on a Molecular Devices ThermoMax microplate o reader. Kinase inhibition for a given compound was expressed as an IC50 value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of phosphorylation in this assay. The range of phosphorylation was calculated from the positive (vehicle plus ATP) and negative (vehicle minus ATP) control values.
5 b. Cellular Tie2 autophosphorylation assay
This assay is based on measuring the ability of compounds to inhibit autophosphorylation of the Tie2 receptor which normally leads to the production of "activated" receptor that in turn initiates the particular signal transduction pathways associated with the receptor function. 0 Autophosphorylation can be achieved by a number of means. It is known that expression of recombinant kinase domains in baculoviral systems can lead to the production of phosphorylated and activated receptor. It is also reported that over expression of receptors in recombinant cell lines can itself lead to receptor autophosphorylation in the absence of the ligand (Heldin C-H. 1995 Cell : 80, 213-223; Blume-J. P, Hunter T. 2001 Nature: 411, 355-65). Furthermore, there are numerous literature examples in which chimaeric receptors have been constructed. In these cases the natural, external cell surface domain of the receptor has been replaced with that of a domain which is known to be readily dimerised via the addition of the appropriate ligand (e.g. TrkA-Tie2/NGF ligand (Marron, M.B., et al., 2000 Journal of Biological Chemistry : 275:39741-39746) or C-fms-Tie-1/CSF-l ligand (Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713). Thus when the chimaeric receptor expressed in a host cell line and the respective ligand is added, this induces autophosphorylation of the chimeric receptor's kinase domain. This approach has the advantage of often allowing a known (and often easily obtained) ligand to be used instead of having to identify and isolate the natural ligand for each receptor of interest.
Naturally if the ligand is available one can use natural cell lines or primary cells which are known to express the receptor of choice and simply stimulate with ligand to achieve ligand induced phosphorylation. The ability of compounds to inhibit autophosphorylation of the Tie2 receptor, which is expressed for example in EA.hy926/B3 cells (supplied by J. McLean/ B. Tuchi, Univ.of N. Carolina at Chapel Hill, CB- 4100, 300 Bynum Hall, Chapel Hill, N.C. 27599-41000, USA) or primary HUVEC (human umbilical vein endothelial cells - available from various commercial sources), can measured by this assay.
Natural Angl ligand can be isolated using standard purification technology from either tumour cell supernatants or alternatively the Angl gene can be cloned and expressed recombinantly using stand molecular biology techniques and expression systems. In this case one can either attempt to produce the ligand either in its native state or as recombinant protein which for example may have been genetically engineered to contain additional of purification tags (eg. polyhistidine peptides, antibody Fc domains) to facilitate the process. Using the ligand stimulation of either EA.hy926/B3 or HUVEC cellular Tie2 receptor as the example, a Angl ligand stimulated cellular receptor phosphorylation assay can be constructed which can be used to analyse to determine the potential of compounds to inhibit this process. For example EA.hy926/B3 cells were grown in the appropriate tissue culture media plus 10% foetal calf serum (FCS) for two days in 6 well plates starting with an initial seeding density of 5x105 cells/well. On the third day the cells were serum starved for a total of 2 hours by replacing the previous media with media containing only 1% FCS. After 1 hour 40 minutes of serum starvation the media was removed and replace with 1 ml of the test compound dilutions (compound dilutions made in serum starvation media yet keeping the DMSO concentration below 0.8%). After 1.5 hours of serum starvation orthovanidate was added to a final concentration of 0.1 mM for the final 10 minutes of serum starvation.
Following a total of 2 hours of serum starvation, the ligand plus orthovandiate was added to stimulate autophosphorylation of the cellular Tie2 receptor (ligand can be added either as purified material diluted in serum starvation media or non-purified cell supernatant containing ligand e.g. when recombinantly expressed mammalian cells). After 10 minutes incubation at 37 0C with the ligand, the cells were cooled on ice washed with approximately 5mls with cold PBS containing 1 mM orthovanadate, after which 1 ml of ice cold lysis buffer ((20 mM Tris pH 7.6, 150 mM NaCl, 50 mM NaF, 0.1 % SDS, 1% NP40, 0.5 % DOC, 1 mM orthovanadate, 1 mM EDTA, 1 mM PMSF, 30 μl / ml
Aprotinin, 10 μg/ml Pepstatin, 10 μg/ml Leupeptin) was addedthe cells and left on ice for 10- 20 minutes. The lysate was removed and transferred to a 1.5 ml Eppendorf tube and centrifuged for 3 minutes at 13000 rpm at 4 0C. 800 μl of each lysate was transferred to fresh 2 ml Eppendorf tubes for the immuno-precipitation. 3 mg = 15 μl of anti-phospho- tyrosine antibody (Santa Cruz PY99 -sc-7020) was added to the lysates and left to incubate for 2 hours at 4 0C. 600 μl washed MagnaBind beads (goat anti-mouse IgG, Pierce 21354) were added to the lysates and the tubes left to rotate over night at 4 0C.
Samples were treated for 1 minute in the magnet before carefully removing the lysis supernatant. 1 ml of lysis buffer was then added to the beads and this step repeated twice more. The beads were suspended in 25 μl of 94 0C hot 2 x Laemmli loading buffer plus beta-mercaptoethanol and left to stand for 15 minutes at room temperature.
The beads were removed by exposing the tubes for 1 minutes in the magnet, and the total liquid separated from the beads from each immuno-precipitate loaded onto Polyacrylamide/SDS protein gels (pre-cast 4-12 % BisTris NuPAGE / MOPS 12 well gels from Novex). Protein gels were run at 200 V and then blotted onto NC membrane for
Ihours30 minutes at 50 V / 250 mA. AU blots were treated with 5% Marvel in PBS-Tween forl hour at room temperature to reduce non-specific binding of the detection antibody. A rabbit anti-Tie2 (Santa Cruz sc-324) was added in a 1:500 dilution in 0.5 % Marvel / PBS- Tween and left to incubate overnight at 4 0C. The blots were rigorously washed with PBS- Tween before adding the goat anti rabbit -POD conjugate (Dako P0448) at a 1:5000 dilution in 0.5 % Marvel / PBS-Tween. The antibody was left on for 1 hour at room temperature before subsequently washing the blots with PBS-Tween. The western blots of the various immuno-precipitated samples were developed the blots with LumiGLO (NEB 7003). And transferred to an X-Ray cassette and films exposed for 15 sec / 30 sec and 60 sec. The relative strength of the protein band which pertains to the phosphorylated Tie2 receptor was evaluated using a FluorS BioRad image analyser system. The percentage phosphorylation for each test compound dilution series was determined from which IC50 values were calculated by standard methods using the appropriate control samples as reference.
Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a) and (b):- l(a):- IC50 in the range, for example, < lOOμM;
Test (b):- IC50 in the range, for example, < 50μM;
By way of example, Table A illustrates the activity of representative compounds according to the invention. Column 2 of Table A shows IC50 data from Test (a) for the inhibition of Tie2 receptor tyrosine kinase in vitro and column 3 shows IC50 data from Test (b) for the inhibition of autophosphorylation of Tie2 receptor tyrosine kinase. Table A:
Figure imgf000078_0001
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula IC, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
The compounds according to the present invention as defined herein are of interest for, amongst other things, their antiangiogenic effect. The compounds of the invention are expected to be useful in the treatment or prophylaxis of a wide range of disease states associated with undesirable or pathological angiogenesis, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. Cancer may affect any tissue and includes leukaemia, multiple myeloma and lymphoma. In particular such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
We believe that the antiangiogenic properties of the compounds according to the present invention arise from their Tie2 receptor tyrosine kinase inhibitory properties. Accordingly, the compounds of the present invention are expected be useful to produce a Tie2 inhibitory effect in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention may be used to produce an antiangiogenic effect mediated alone or in part by the inhibition of Tie2 receptor tyrosine kinase. More particularly the compounds of the invention are expected to inhibit any form of cancer associated with Tie2. For example, the growth of those primary and recurrent solid tumours which are associated with Tie2, especially those tumours which are significantly dependent on Tie2 receptor tyrosine kinase for their growth and spread. According to a further aspect of the invention there is provided a compound of the
Formula IC, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore, for use as a medicament.
According to another aspect of the invention, there is provided the use of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of an anti-angiogenic effect in a warm-blooded animal such as man.
According to another aspect of the invention, there is provided the use of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancers in a warm-blooded animal such as man.
According to another aspect of the invention, there is provided the use of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid and skin cancer in a warm-blooded animal such as man.
According to another aspect of the invention there is provided a method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, (such as a compound of formula IC) or a pharmaceutically acceptable salt thereof, as defined hereinbefore. According to another aspect of the invention there is provided a method of treating cancers in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a method of treating a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid or skin cancer, in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man.
According to an another aspect of the invention there is provided a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in producing an anti-angiogenic effect in a warm-blooded animal, such as man.
According to another aspect of the invention there is provided a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of cancer.
According to another aspect of the invention there is provided a compound of the formula I (such as a compound of formula IC), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid or skin cancer. As hereinbefore mentioned it is further expected that a compound of the present invention will possess activity against other diseases mediated by undesirable or pathological angiogenesis including psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. The anti-angiogenic activity defined herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
(ii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734 such as
(2S)-2-{o-fluoro-p_-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)- N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(iii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example the EGFR tyrosine kinase inhibitors N-(3- chloro-4-fluorophenyl)-7-methoxy- 6-(3-moφholinopropoxy)quinazolin-4-amine (ZDl 839), N-(3-ethynylphenyl)-
6,7-bis(2-methoxyethoxy)quinazolin-4-amine (CP 358774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents that work by different mechanisms to those defined hereinbefore, such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) biotherapeutic therapeutic approaches for example those which use peptides or proteins (such as antibodies or soluble external receptor domain constructions) which either sequest receptor ligands, block ligand binding to receptor or decrease receptor signalling (e.g. due to enhanced receptor degradation or lowered expression levels) (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, including for example ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytoldne-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. ' According to this aspect of the invention there is provided a pharmaceutical product comprising a compound of the Formula I as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
In addition to their use in therapeutic medicine, the compounds of Formula I and their pharmaceutically acceptable salts, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (0C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0C;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals;
4.5-30 mmHg) with a bath temperature of up to 60 0C;
(iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates;
(iv) in general, the course of reactions was followed by TLC and / or analytical LC-MS, and reaction times are given for illustration only;
(v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSOd6) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;
(viii) chemical symbols have their usual meanings; SI units and symbols are used;
(ix) solvent ratios are given in volume:volume (v/v) terms; and
(x) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is MH+;
(xi) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulphur atom have not been resolved; (xii) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example;
(xvi) the following abbreviations have been used:
AcOH Acetic acid
AIBN 2,2'-Azobisisobutyronitrile
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMA N,N-Dimethylacetamide
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
DMTMM 4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4-methyhnorpholin-4-ium chloride dppf 1 , 1 ' -Bis(diphenylphosphino)ferrocene
EtOAc Ethylacetate
HATU O-(7-Azabenzotriazol- 1 -yl)-Ν,Ν,Ν' ,N'-tetramethyluronium hexafluorophosphate 'PrMgCl Isopropylmagnesium chloride
LDA Lithium diisopropylamide
LHMDS Lithium bis(trimethylsilyl) amide
777-CPBA metø-Chloroperbenzoic acid
MeOH Methanol
MeCN Acetonitrile
MCX Mixed cation exchange resin
MTBE Methyl tert-butyl ether
LCMS Liquid Chromatograpy - Mass Spectrometry
NMP l-Methyl-2-pyrrolidinone
POCl3 Phosphorus oxychloride
RPHPLC Reversed phase high peformance liquid chromatography
TFA Trifluoroacetic acid
THF Tetrahydrofuran
xvii) where a synthesis is described as leading to an acid addition salt (e.g. HCl salt), no comment is made on the stoichiometry of this salt. Unless otherwise stated, all NMR data is reported on free-base material, with isolated salts converted to the free-base form prior to characterisation.
Example 1 N-(5-tert-butylisoxazol-3-yl)-N'-[3-(pyrimidin-5-ylethynyl)phenyl]urea
Figure imgf000086_0001
Phenyl (5-tert-butylisoxazol-3-yl)carbamate (Intermediate 2) (160 nig) was added to a stirred solution of [3-(pyrimidin-5-ylethynyl)phenyl]amine (Intermediate 1) (100 mg) and triethylamine (0.086 mL) in THF (10 niL). The reaction mixture was heated at 75°C for 4 hours. The solvent was evaporated and the residue triturated with ether (20 mL) and the resultant solid was purified by flash chromatography on silica using 0-10% MeOH in DCM as eluent. The resultant product was triturated with ether (20 mL) to give the title compound as a colourless solid (120 mg, 65%);
1H NMR (DMSO-de) 1.29 (s, 9H), 6.50 (s, IH), 7.21 - 7.29 (m, IH), 7.34 - 7.45 (m, 2H), 7.85 (s, IH), 8.94 (s, IH), 9.02 (s, 2H), 9.19 (s, IH), 9.58 (s, IH) MS m/e (M+H)+ 362.
Intermediate 1 3-(pyrimidin-5-ylethynyl)phenyl] amine
Figure imgf000087_0001
Palladium (10 wt.% on activated carbon) (0.2 g) was added to a stirred solution of 5- bromo-pyrimidine (2.0 g) and 3-ethynylaniline (1.47 g) in DIPEA (50 mL) under an inert atmosphere. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered through diatomaceous earth and washed with DCM. The filtrate was purified by flash chromatography on silica using 0-50% EtOAc in DCM as eluent to give the title compound as a beige solid (0.7 g, 28%);
1H NMR (DMSO-d6) 5.29 (s, 2H), 6.64 (m, IH), 6.71 (d, IH), 6.74 - 6.79 (m, IH), 7.08 (t, IH), 8.96 (s, 2H), 9.16 (s, lH) MS m/e (M+CH3CN)+ 237. Intermediate 2
Phenyl (5-tert-butyIisoxazol-3-yl)carbamate
Figure imgf000088_0001
Phenyl chloroformate (52 mL) was added dropwise to a solution of 3-amino-5-tert- butylisoxazole (52.3 g) in THF (1.0 L) and pyridine (60 mL) at O0C. When the addition was complete water (500 mL) was added and the reaction mixture stirred for 45 mins while warming to ambient temperature, before extracting into ether (3 x 300 ml). The combined organics were washed with water, brine and concentrated in vacuo, azeotroping with toluene and chloroform to give the title compound as a colourless solid (96.3 g, 99%). 1H NMR (DMSOd6) 1.28 (s, 9H), 6.42 (s, IH), 7.18-7.26 (m, 3H), 7.39-7.45 (m, 2H), 11.13 (bs, IH); MS m/e MH+ 261.
Example 2
N-{3-[(6-aminopyridin-3-yl)ethynyl]phenyl}-N'-(5-tert-butylisoxazol-3-yl)urea
Figure imgf000088_0002
2-Amino-5-iodopyridine (220 mg) and N-(5-tert-butylisoxazol-3-yl)-N'-(3- ethynylphenyl)urea (Intermediate 3) (283 mg) were dissolved in DMF (8 mL) and triethylamine (2 mL) and degassed with nitrogen for 15 min. Palladium(II)(dppf)chloride (37 mg) and CuI (4 mg) were added and the mixture stirred at ambient temperature for 1.5 hr. After precipitation into water, the crude product was collected by filtration, washed with water and the solid dried in vacuo. Purification by flash chromatography using 0-50% EtOAc in DCM as eluent gave the title compound as a colourless solid (134 mg). 1H NMR (DMSOd6) 9.55 (s, IH), 8.85 (s, IH), 8.15 (s, IH), 7.7 (s, IH), 7.5 (m, IH), 7.3
(m, 2H), 7.05 (m, IH), 6.5 (s, IH) 6.4 (s, 2H), 1.28 (s, 9H).
MS m/e MH+376.
Intermediate 3 N-(5-tert-butylisoxazol-3-yl)-Λ^-(3-ethynylphenyl)urea
Figure imgf000089_0001
A solution of 5~ter?-butylisoxazol-3 -amine (1.4 g) and di-succinimidyl carbonate (2.56 g) in MeCN (30 mL) was heated to 8O0C for 4 hours. The solution was cooled to ambient temperature, 3-ethynylaniline (1.17 g) added and the mixture heated for a further 16 hours at 800C. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between ether and water, the organic phase washed with water and then concentrated in vacuo. Trituration from iso-hexane gave the title compound as a colourless solid (1.57 g);
1H NMR (DMSOd6) 9.53 (s, IH), 8.87 (s, IH), 7.65 (d, IH), 7.29 (t, IH), 7.11 (d, IH), 6.49 (s, IH), 4.14 (s, IH), 1.28 (s, 9H); MS nVe MH+ 284.
The following Examples were prepared in a similar way to Example 2
Example 3 N-2{3-[(2-aminopyridin-3-yl)ethynyl]phenyl}-N'-(5-tert-butylisoxazol-3-yl)urea
Figure imgf000089_0002
SM: Intermediate 3, 2-amino-3-iodopyridine 1H NMR (DMSO-Cl6) 9.55 (s, IH), 8.85 (s, IH), 7.75 (s, IH), 7.6 (m, IH), 7.2-7.4 (m, 4H), 6.6 (s, IH), 6.5 (s, IH), 6.3(s, 2H), 1.28 (s, 9H). MS m/e MH+ 376.
Example 4
N-(5-tert-butylisoxazol-3-yl)-N'-[3-(lH-pyrazol-4-ylethynyl)phenyl]urea
Figure imgf000090_0001
SM: Intermediate 3, 4-iodo-lH-pyrazole 1H NMR (DMSO-d6) 13.1 (s, IH), 9.55 (s, IH), 8.55 (s, IH), 7.9 (s, 2H), 7.7 (s, IH), 7.3 (m, 2H), 7.1 (m, IH), 6.5 (S, IH), 1.28 (s, 9H). MS m/e MH+ 350.
Example 5 N-{3-[(5-aminopyrazin-2-yl)ethynyl]phenyl}-N'-(5-tert-butylisoxazol-3-yl)urea
Figure imgf000090_0002
SM: Intermediate 3, 5-bromopyrazine-2-amine
1H NMR (DMSO-de) 9.55 (s, IH), 8.9 (s, IH), 8.15 (s, IH), 7.9 (s, IH), 7.7 (s, IH), 7.35 (m, 2H), 7.15 (m, IH), 6.9 (s, 2H), 6.5 (s, IH), 1.28 (s, 9H). MS m/e MH+ 377. Example 6
N-(5-{[3-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]ethynyl}-l,3- thiazole-2-yl)acetamide
Figure imgf000091_0001
SM: Intermediate 3, l-(5-bromo-l,3-thiazol-yl) ethanone
1H NMR (DMSO-d6) 12.4 (s, IH), 9.55 (s, IH), 8.9 (s, IH), 7.8 (s, IH), 7.7 (s, IH), 7.35
(m, 2H), 7.15 (m, IH), 6.5 (s, IH), 2.15 (s, 3H), 1.28 (s, 9H).
MS m/e MH+ 424.
Example 7 N-{3-[(6-aminopyridazin-3-yl)ethynyl]phenyl}-N'-(5-tert-butylisoxazol-3-yl)urea
Figure imgf000091_0002
SM: Intermediate 3, 6-bromopyridazme-3-amine
1H NMR (DMSOd6) 9.55 (s, IH), 8.9 (s, IH), 7.8 (s, IH), 7.4 (m, 4H), 7.2 (m, IH), 6.8 (s, 2H), 6.5 (s, IH), 1.28 (s, 9H).
MS m/e MH+ 377. Example 8
N-(5-{[3-({[(5-tert-buylisoxazol-3-yl)amino]carbonyl}amino)phenyl]ethynyl}pyridin-
2-yl)acetamide
Figure imgf000092_0001
A solution of N-{3-[(6-aminopyridin-3-yl)ethynyl]phenyl}-N'-(5-tert-butylisoxazol-3- yl)urea (Example 2) (420 mg) in DMF (4 niL), triethylamine (1 mL), glacial AcOH (0.11 mL) and POCI3 (0.19 mL) was heated at 650C for 16 hr. After precipitation with water, the crude product was collected by filtration, washed with water and dried in vacuo. Purification by flash chromatography, using 0-100% EtOAc in DCM afforded the title compound as a colourless solid (30 mg).
1H NMR (DMSO-d6) 10.68 (s, IH), 9.55 (s, IH), 8.9 (s, IH), 8.5 (s, IH), 8.1 (m, IH), 7.8 (s, IH), 7.35 (m, 3H), 7.2 (m, IH), 6.5 (s, IH), 2.1 (s, 3H), 1.28 (s, 9H). MS m/e MH+418.
The following Examples were prepared in a similar way to example 8
Example 9
N-(5-{[3-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]ethynyl}pyridin- 2-yl)~2-(2-methoxyethoxy)acetamide
Figure imgf000092_0002
SM: Example 2, 2-methoxyethoxyacetic acid Η NMR (DMSO-d6) 10.13 (s, IH), 9.95 (s, IH), 8.9 (s, IH), 8.5 (s, IH), 8.15 ( m, IH), 8.0 (m, IH), 7.8 (s, IH), 7.35 (m, 3H), 7.2 (M, IH), 6.5 (s, IH) 4.15 (s, 2H)3 3.7 (m, 2H), 3.5 (m, 2H), 3.3 (s, 3H obscured by H2O), 1.28 (s, 9H). MS nVe MH+ 492.
Example 10
N-(5-{ [3-({ [(5-tert-butylisoxazol-3-yl)amino] carbonyl} amino)phenyl] ethynyl}pyrazin- 2-yl)acetamide
Figure imgf000093_0001
SM: Example 5, acetic acid (reaction temperature increased to 9O0C) 1H NMR (DMSO^6) 10.98 (s, IH), 9.6 (s, IH), 9.35 (s, IH), 8.95 (s, IH), 8.65 (s, IH), 7.8 (s, IH), 7.4 (m, 2H), 7.25 (m, IH), 6.5 (s, IH), 2.15 (s, 3H), 1.28 (s, 9H). MS mZe MH+ 419.
Example 11
N-(5-{ [3-({ [(5-tert butylisoxazol-3-yl)amino] carbonyl} amino)phenyl] ethynyl}pyrazin- 2-yl)-2-(2-methoxyethoxy)acetamide
Figure imgf000093_0002
SM: Example 5, 2-methoxyethoxyacetic acid
1H NMR (DMSOd6) 10.55 (s, IH), 9.6 (s, IH), 9.35 (s, IH), 8.95 (S, IH), 8.65 (s, IH), 7.8 (s, IH), 7.4 (m, 2H), 7.25 (m, IH), 6.5 (s, IH), 4.2 (s, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.3 (s, 3H obscured by H2O), 1.28 (s, 9H). MS nVe MH+ 493.
Example 12 N-(5-tert-butylisoxazol-3-yl)-N'-{3-[(4-methoxypyrimidin-5-yl)ethynyl]phenyl}urea
Figure imgf000094_0001
A solution of N-(5-tert-butylisoxazo\-3-yϊ)-IΨ- {3~[(4-chloropyrimidin-5- yl)ethynyl]phenyl}urea (Intermediate 4) (200 mg) in 7Ν NH3 in MeOH (10 mL) was stirred at ambient temperature for 5 days. The solution was filtered and concentrated in vacuo. The residue was dissolved in ether, filtered, and then purified by RPHPLC (H2OrMeCN, 10-90%) to give the title compound as a colourless solid (27 mg); 1H NMR (DMSO-d6) 1.29 (s, 9H), 4.04 (s, 3H), 6.50 (s, IH), 7.20 (d, IH), 7.33-7.40 (m, 2H), 7.79 (s, IH), 8.75 (s, IH), 8.80 (s, IH), 8.95 (s, IH), 9.58 (s, IH); MS m/e MH+ 392.
Intermediate 4 N-(5-te/^-butylisoxazol-3-yl)-iV-{3-[(4-chloropyrimidin-5-yl)ethynyl]phenyl}urea
Figure imgf000094_0002
Bis(triphenylphosphine)palladium dichloride (170 mg), CuI (12.5 mg) and triethylamine (10 mL) were added to a degassed solution of 4-chloro-5-iodopyrimidine (Chem.Pharm.Bull. 1986, 34(7), 2719-2724) (2.40 g) andN-(5-fert-butylisoxazol-3-yl)-JV- (3-ethynylphenyl)urea (Intermediate 3) (3.1 g) in DMF (50 mL) and then heated at 5O0C for 1.5 hours. The reaction mixture was concentrated, water added and then extracted into DCM. The organic layer was washed with water then brine and concentrated in vacuo to give the title compound as a brown foam (4.50 g) which was used without further purification. MS m/e MH+ 396 (35Cl), 398 (37Cl).
Example 13
N-(5-tert-butylisoxazol-3-yl)-N'-{3-[(6-oxo-l,6-dihydropyrimidin-5- yl)ethynyl]phenyl}urea
Figure imgf000095_0001
A solution of N-(5-ter^-butylisoxazol-3-yl)-./V- {3-[(4-chloropyrimidin-5- yl)ethynyl]phenyl}urea (Intermediate 4) (600 mg) and 2M HCl (5 ml) in THF (10 ml) was heated at 5O0C for 10 hours and then concentrated in vacuo. The residue was dissolved in DCM, washed with 50% saturated aqueous NaHCO3 and concentrated in vacuo. The residue was purified by flash chromatography on silica using 0-10% ((10% 7N NH3 in MeOH) in MeOH) in DCM as eluent and then purified by RPHPLC (H2OiMeCN, 10-90%) to give the title compound as a colourless solid (62 mg); 1H NMR (DMSO-d6) 1.30 (s, 9H), 6.55 (s, IH), 7.42-7.50 (m, 2H), 7.66 (d, IH), 8.20 (s, IH), 8.96 (s, IH), 9.03 (s, IH), 9.17 (s, IH), 9.59 (s, IH); MS m/e MH+ 378.

Claims

1. The use of a compound of the Formula I:
Figure imgf000096_0001
Formula I wherein:
A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
B represents a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulphur and which is saturated, partially saturated or aromatic;
D represents 5 or 6 membered nitrogen-containing heteroaryl ring which optionally comprises 1 or 2 or 3 further heteroatoms independently selected from oxygen, nitrogen or sulphur;
L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-,
-C(RaRb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(RaRb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-,
-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-,
-N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or -S(O)2N(R9)-(CRaRb)x-Z-(CRaRb)y-,
-N(R8)C(O)-O-(CRaRb)x-Z-(CRaRb)y- or -O-C(O)-N(R9)-(CRaRb)x-Z-(CRaRb)y-; wherein Z is a direct bond, -O- or -N(R8)- wherein x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4 and where L is a group -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- where Z is a group -N(R8)-, then x is other than 0, wherein R8 and R9 represents hydrogen or (l-6C)alkyl, wherein Ra and Rb independently represent hydrogen or (l-6C)alkyl or Ra and Rb together with the carbon atom to which they are attached represent (3-6C)cycloalkyl; and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halogeno, cyano, hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring
R1 is selected from hydrogen, hydroxy, (l-6C)alkyl, (l-6C)allcoxy or (3-7C)cycloalkyl wherein the (l-6C)alkyl, (l-6C)alkoxy and the (3-7C)cycloalkyl groups are optionally substituted by one or more groups independently selected from halo, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or R1 represents a group -NR2R3 as defined below;
p is 0, 1, 2 or 3;
R2 and R3 are independently selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-όC)alkyl, (l-6C)alkoxycarbonyl,
(3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6 , or a 5 or 6 membered heteroaryl ring, or R2 and R3 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein a (l-6C)alkyl, the (l-6C)alkoxy, the (l-6C)alkanoyl and the
(3-6C)cycloalkyl groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or -N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (l-6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy(l-6C)allcoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, mono(l-6C)alkylcarbamoyl, di- [(l-6C)alkyl]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more hydroxy groups; wherein the phenyl is optionally substituted by one or more groups independently selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, wherein the (l-6C)alkyl and (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)2R4 wherein z is 0, 1, 2 or 3 and R4 is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy;
R5 is selected from cyclopropyl, cyano, halo, (l-6C)alkoxy or (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or by one or more fluoro;
n is O, 1, 2 or 3; R6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, -S(0)q-(l-6C)alkyl wherein q is 0, 1 or 2, -N(R°)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl, -S(O)q-(l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl or hydroxy(l-6C)alkyl; and
m is 0, 1, 2 or 3;
and when B is a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10 membered bicyclic group, the rings and bicyclic group optionally bear 1 or 2 oxo or thioxo substituents; and salts or solvates thereof, with the proviso that: (i) when D is pyrimidin-5-yl, the 4-position of the pyrimidin-5-yl is substituted by R1, the 6-position of the pyrimidin-5-yl is substituted by -NR2R3, and L is -C(RaRb)C(O)N(R9)-, -N(R8)C(O)C(RaRb)-, -N(R8)C(O)N(R9)-, -N(R8)C(O)O-, or -OC(O)-N(R9)- and a (l-6C)alkyl group in Ra or Rb is unsubstituted then the 2-position of the pyrimidin-5-yl cannot be substituted by hydrogen, (l-6C)alkyl or (l-6C)alkoxy; (ii) when L represents -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or
-S(O)2N(R8)-(CRaRb)χ-Z-(CRaRb)y-, where x+y > 0, D is pyrimidin-5-yl, and one of R1 is a group NR2R3, then p is 3 and the other two R1 groups are also NR2R3 groups; (iii) when L is -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- where x + y>0, D is pyrimidin-5- yl and one of R1 is a group NR2R3, then p is 3 and the other two R1 groups are also NR2R3 groups;
(iv) where L represents -C(RaRb)C(O)N(R9)-, -N(R8)C(O)C(RaRb)~, -N(R8)C(O)N(R9)-, -N(R8)C(O)O-, or-OC(O)-N(R9)-, D is pyrimidin-5-yl, and the 2-position of the pyrimidinyl-5-yl is substituted by -NR2R3, then both the 4-position and 6-position of the pyrimidin-5-yl must be substituted by -NR2R3, in the preparation of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
2. The use according to claim 1 wherein D is selected from pyrimidinyl, pyridyl, pyrazolyl, pyrazinyl, thiazolyl and pyridazinyl.
3. The use according to claim 1 wherein A is phenyl.
4. The use according to claim 1 wherein L is
-N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, where R8, R9, Ra, Rb, Z, x and y are as defined in claim 1.
5. The use according to claim 1 wherein B is a 5 or 6 membered heteroaryl ring.
6. The use according to any one of the preceding claims wherein the compound of formula (I) is a compound of formula (Ib)
Figure imgf000100_0001
Formula Ib wherein
A is selected from phenyl or pyridyl;
B is selected from isoxazolyl or pyrazolyl;
D is selected from pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; and R1, R2, R3, R5, R6, L, n, m and p are as defined in claim 1, and salts thereof.
7. A compound of formula (IC)
Figure imgf000101_0001
(IC)
where A, B, D, R1, R5, R6, p, n and m as defined above in claim 1, subject to the following provisos:
A) when L is a group -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or
N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, then at least one of x or y is other than 0, or Z is other than a direct bond;
B) where L is a group C(RaRb)C(O)N(R8)-(CRaRb)x-Z-(CRaRb)y, x is 0, y is 0 and Z is a direct bond, then B is other than a substituted l,4,5,6-tetrahydro-cyclopentapyrazol-3-yl group
C) when L is meta on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)r, -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or - -N(R8)C(O)-O-(CRaRb)x-Z-(CRaRb)y- where x and y are both 0 and Z is a direct bond, then ring A is other than a thiazolyl ring;
D) when L is -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)r, where Z is a direct bond, then x + y is other than 1,
E) when L is a group -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y- or -S(O)2N(R9)-(CRaRb)x-Z-(CRaRb)y-, and x and y are both 0 and Z is a direct bond, then D is other than a thiazole group, and
F) when L is a group -N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, where x and y are both zero and Z is a direct bond, and where B is a 6-membered aryl group, a 6 membered nitrogen containing heteroaryl group, or a 9 or 10 membered bicyclic group which contains nitrogen atoms, then R6 is other than an optionally substituted N-linked pyrolidine group.
8. A compound according to claim 7 wherein L is a group C(RaRb)C(O)N(R8)- (CRaRb)x-Z-(CRaRb)y, then at least one of x or y is other than 0, or Z is other than a direct bond.
9. A compound according to claim 7 wherein L is a group
-N(R8)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)r, where R8, R9, Ra, Rb, Z, x and y are as defined in claim 1.
10. A compound according to any one of claims 7 to 9 wherein D is selected from pyrimidinyl, pyridyl, pyrazolyl, pyrazinyl, thiazolyl and pyridazinyl.
11. A compound according to any one of claims 7 to 10 wherein A is phenyl. 0
12. A compound according to any one of claims 7 to 10 wherein B is a 5 or 6 membered heteroaiyl ring.
13. A compound according to claim 12 wherein B is isoxazolyl or pyrazolyl. 5
14. A compound according to any one of claims 7 to 13 for use in therapy.
15. A pharmaceutical composition comprising a compound according to any one of claims 7 to 14 in combination with a pharmaceutically acceptable diluent or carrier. o
16. A method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. 5
17. A method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. 0
18. A method of treating cancers in a warm-blooded animal, in need of such treatment, which comprises administering to said animal an effective amount of a according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
19. The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim I3 in the manufacture of a medicament for use in the production of an anti-angiogenic effect in a warm-blooded animal.
20. The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 in the manufacture of a medicament for use in the treatment of cancers in a warm-blooded animal.
21. A process for preparing a compound of formula (IC) as defined in claim 7, which process comprises one of the following: Process fa) for compounds of the formula IC wherein L is
-N(R8)C(O)N(H)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula II:
Figure imgf000103_0001
wherein R1, R5, R8, n, p, D and A are as defined in claim 7 except that any functional group is protected if necessary, with an isocyanate of the formula III:
Figure imgf000103_0002
wherein R6, Ra, Rb, Z, x, y m, B and Z are as defined in claim 7 except that any functional group is protected if necessary; or Process (b) for compounds of the formula IC wherein L is
-N(R8)C(O)N(H)-(CRaRb)χ-Z-(CRaRb)y-, the reaction of a compound of the formula II as defined above with an aryl carbamate of the formula IV:
Figure imgf000104_0001
IV wherein Ar is a suitable aryl group, for example phenyl, and R6, Ra, Rb, x, y, m and B are as defined in claim 7 except that any functional group is protected if necessary; or
Process (c) for compounds of the formula IC wherein L is - -NN((RR88))CC((OO))--((CCRRaaRRb°))xx--ZZ--((CCRRaaRRbD))yy-- oorr --CCC(R aaτR>bB \)N(R8)C(O)-(CRaRD)x-Z-(CRaR°)y-, the reaction of a compound of the formula V:
Figure imgf000104_0002
V
wherein W is -C(RaRb)- or a direct bond and R1, R5, R8, Ra, Rb, n, p, A and D are as defined in claim 7 except that any functional group is protected if necessary, with a heterocycle of the formula VI:
Figure imgf000104_0003
Vl wherein Lg2 is a suitable displaceable group and R6, Ra, Rb, Z, m, x, y and B are as defined in claim 7 except that any functional group is protected if necessary; or Process (d) for compounds of the formula IC wherein L is
-N(R8)C(O)N(H)-(CRaRb)x-Z-(CRaRb)y- the reaction of a compound of the formula II as defined above with a trichloroacetylamine of the formula VII:
Figure imgf000105_0001
VII wherein R6, Ra, Rb, x, y, m, B and Z are as defined in claim 7 except that any functional group is protected if necessary; or
Process (e) for compounds of the formula IC wherein L is -N(H)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of an isocyanate of the formula VIII:
Figure imgf000105_0002
VIII wherein R1, R5, n, p, A and D are as defined in claim 7 except that any functional group is protected if necessary, with an amine of the formula IX
Figure imgf000105_0003
IX wherein R6, R9, Ra, Rb, m, x, y, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary,or Process ffl For compounds of the formula IC wherein L is -N(H)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula X:
Figure imgf000106_0001
X wherein Ar is a suitable aryl group, for example phenyl, and R1, R5, n, p, A and D are as defined in claim 7 except that any functional group is protected if necessary, with an amine of the formula IX as defined above. Process Cg) For compounds of the formula IC wherein L is -C(RaRb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula XI:
Figure imgf000106_0002
Xl wherein Lg2 is a displaceable group, W is -C(RaRb)- or a direct bond and R1, R5, Ra,
R , n, p i,, AA aanndd DD aarree aass ddeeffiinneedd iinn ccllaaiimm 77 eexxicept that any functional group is protected if necessary, with an amine of the formula XII:
Figure imgf000106_0003
XII wherein Z, R6, R9, Ra, Rb, m, x, y and B are as defined in claim 7 except that any functional group is protected if necessary; or
Process (h) for compounds of the formula IC wherein L is N(R8)C(O)-O-, the reaction of a compound of the formula II as defined above with a compound of the formula XIII:
Figure imgf000107_0001
XIII wherein Lg1 is a displaceable group, and R6, m and B are as defined in claim 7 except that any functional group is protected if necessary; or
Process (T) for compounds of the formula IC wherein L is -N(R8)S(O)2-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula XIV:
Figure imgf000107_0002
XIV wherein R1, R5, R8, n, p, A and D are as defined in claim 7 except that any functional group is protected if necessary, with an activated sulphonyl of the formula XV:
Figure imgf000107_0003
wherein R6, Ra, Rb, x, y m, Z and B are as defined in claim 7 except that any functional group is protected if necessary and wherein Lg1 is a displaceable group; or
Process (j) for compounds of the formula IC wherein L is -S(O)2N(R8)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula XVI
Figure imgf000107_0004
XVI wherein R1, R5, n, p, A and D are as defined in claim 7 and Lg1 is a displaceable group except that any functional group is protected if necessary, with an amine of the formula XVII:
Figure imgf000108_0001
XVII wherein R6, R8, Ra, Rb, x, y m, Z and B are as defined in claim 7 except that any functional group is protected if necessary; or
Process (k) for compounds of formula IC wherein Z is -O- or -N(Ra)-, the reaction of a compound of formula XVIII
H
Figure imgf000108_0002
XVIII wherein Y is -S(O)2N(R8)- or -N(R8)S(O)2- and R1, R5, R8, Ra, Rb, n, p, x, y, A, and D are as defined in claim 7 except that any functional group is protected if necessary, with a compound of formula XIX,
Figure imgf000108_0003
XIX wherein Lg1 is a displaceable group, and R6, Ra, Rb, y, m and B are as defined in claim 7 except that any functional group is protected if necessary; Process (1) for compounds of formula IC wherein Z is -O- or -N(Ra)-, the reaction of a compound of formula XX
Figure imgf000109_0001
XX wherein Y is -S(O)2N(R8)- or ~N(R8)S(O)2- and Lg2 is a displaceable group, and R1, R5, R8, Ra, Rb, n, p, x, A and D are as defined in claim 7 except that any functional group is protected if necessary,with a compound of formula XXI,
Figure imgf000109_0002
XXI wherein R6, Ra, Rb, m, y and B are as defined in claim 7 except that any functional group is protected if necessary; or
Process (m) for compounds of formula IC wherein an R1 group is -NR2R3 The reaction of a compound of the formula XXII:
Figure imgf000109_0003
XXII wherein Lg3 is a displaceable group and R1, R5, R6, n, m, p, A, B, D and L are as defined in claim 7 except that any functional group is protected if necessary, with an amine of the formula HNR2R3, wherein R2 and R3 are as defined in claim 7 except that any functional group is protected if necessary; or Process (n) fhe reaction of a compound of the formula XXIII:
Figure imgf000110_0001
XXIII wherein Lg4 is a displaceable group and R5, R6, n, m, A, B and L are as defined in claim 7 except that any functional group is protected if necessary, with an heterocyle of the formula XXIV:
Figure imgf000110_0002
XXIV wherein R , p and D are as defined in claim 7 except that any functional group is protected if necessary; or
Process (ό) the reaction of an alkyne of the formula XXV:
Figure imgf000110_0003
XXV wherein R5, R6, n, m, A, B and L are as defined in claim 7 except that any functional group is protected if necessary, with a heterocycle of the formula XXVI:
Figure imgf000110_0004
XXVI wherein Lg5 is a displaceable group and R1, p and D are as defined in claim 7 except that any functional group is protected if necessary; and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt or solvate.
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